5-heteroarylamino-6-oxy-substituted 3(2H)-pyridazinones

ABSTRACT

A compound of the formula: ##STR1## or its pharmaceutically acceptable salt and pharmaceutical compositions containing these compounds as effective ingredients. These compounds have strong antithrombotic activity, cardiotonic activity, vasodilator activity and anti-SRS-A activity, and are useful as prophylactic or therapeutic agents for various thrombotic afflictions, congestive heart failure, hypertension, asthma, immediate-type allergy diseases and the like.

This is a division of application Ser. No. 07/768,182, filed on Oct. 16, 1991, U.S. Pat. No. 5,202,323.

TECHNICAL FIELD

The present invention relates to novel 3(2H)-pyridazinone derivatives and their pharmaceutically acceptable salts having an inhibitory activity of platelet aggregation, a cardiotonic activity, a vasodilating activity and an anti-SRS-A activity, processes for their preparation and pharmaceutical compositions containing them as active ingredients.

BACKGROUND ART

1) Field of anti-thrombotic agent

It is known that platelet aggregation plays an important role for thrombus formation in connection with a disease state. Various thrombotic diseases caused by thrombus formation mainly include cerebral thrombosis, pulmonal thrombosis, myocardial infarction, angina pectoris, occlusion of peripheral artery and the like, and all of these diseases require development for useful drugs. As a prophylactic or therapeutic drug, an anti-thrombotic agent having an inhibitory activity of platelet aggregation draws public tension. Heretofore, the effect of aspirin has been widely studied, and more recently ticlopidine and cilostazol have been clinically developed. However, a more strongly effective drug is demanded in respect of its effects.

In addition to the above-mentioned various thrombotic diseases, there are enumerated various diseases in relation to platelets. Examples for these diseases include nephritis, cancer cell metastasis and the like, and recently various studies have been conducted with regard to prophylactic or therapeutic effects for these diseases achieved mainly by an anti-thrombotic agent having an activity for controlling platelet function ("Journal of Royal College of Physicians", Vol. 7, No. 1, p. 5-18, 1972; "Japan Clinics (Nihon Rinsho)", Vol. 4, No. 6, p. 130-136, 1988; Anticancer Research, Vol 6, p. 543-548, 1986).

2) Field of cardiotonic agent

A cardiotonic agent to enhance myocardial contractive force have been used as a therapeutic drug for congestive heart failure from old times. However, conventional cardiotonic agents such as cardiac glycosides represented by digitalis, aminophylline and catecholamines have strong side effects, and therefore drugs such as milrinone and denopamine are recently clinically developed.

3) Field of vasodilator

There are many known vasodilators, but at present there are few drugs which have beneficial pharmacologic properties for circulatory system such as a satisfactory inhibitory activity of platelet aggregation.

4) Field of anti-SRS-A agent

SRS-A (Slow Reacting Substances of Anaphylaxis) is a chemical mediator released together with histamine, etc. by an allergic reaction and has pharmacological activity to cause a strong and prolonged contraction of tracheal smooth muscle. Their existence has long been known from such a phenomenal aspect.

It was found in 1979 that SRS-A itself is a mixture of leukotriene C₄ (hereinafter referred to as LTC₄), leukotriene D₄ (hereinafter referred to as LTD₄) and leukotriene E₄ (hereinafter referred to as LTE₄) [generally called peptide leukotriene].

Extensive researches have been conducted on SRS-A for its relationship with a disease state. As a result, the relationship of SRS-A with immediate type allergic diseases such as bronchial asthma, allergic rhinitis, urticaria and hay fever, has become clear.

Further, the relationship of SRS-A with various inflammatory diseases, ischemic heart diseases, etc., has been suggested.

Therefore, a compound which exhibits inhibition against SRS-A, is expected to be useful as a prophylactic or therapeutic drug against the disorders caused by either LTC₄, LTD₄ or LTE₄, or by a mixture thereof.

As the SRS-A antagonists, many medicinal substances have been reported. ("Drugs of the Future", Vol. 12, p. 453-474 (1987); "Annual Reports in Medicinal Chemistry", Vol. 22, p. 73-84 (1987) and "Annual Reviews in Pharmacological Toxicology", Vol. 29, p. 123-143 (1989)).

However, no instance of their practical clinical application has been reported.

Now, the relationship of 6-ω-substituted alkyloxy-3(2H)-pyridazinones of the formula [I] and their pharmaceutically acceptable salts thereof according to the present invention with compounds disclosed in published references will be described.

(a) German Laid Open Patent Application No. 1,670,169 (hereinafter referred to as reference (a)) discloses 3(2H)-pyridazinones having hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic group at 2-position, chlorine or bromine at 4-position, an aralkylamino group at 5-position, and chlorine, bromine, a hydroxy or C₁ -C₄ alkoxy group at 6-position.

This reference (a) discloses a process for the synthesis of 3(2H)-pyridazinone derivatives, their application to agricultural chemicals, their application as intermediates for medicines or dyestuffs, or their application as intermediates for various compounds. However, no mention is made to their pharmacological activities, and no specific examples are given for such compounds. Further, such compounds are not specifically described.

(b) Japanese Unexamined Patent Publication No. 183675/1983 (hereinafter referred to as reference (b)) discloses 3(2H)-pyridazinone derivatives having a lower alkyl group at the 2-position, a hydrogen atom at the 4-position, a substituted or non-substituted anilino group at the 5-position and a hydroxyl group or a lower alkoxy group at the 6-position.

The 3(2H)-pyridazinone derivatives are disclosed to have analgesic action, anti-inflammatory action, anti-allergic action and anti-rheumatic action, but there is no disclosure concerning pharmacological activities.

(c) Japanese Unexamined Patent Publication No. 30187/1988, European Laid Open Patent Publication No. 0275997 (corresponding U.S. Pat. No. 4,978,665) (hereinafter referred to as reference (c)) discloses 6-substituted alkoxy-5-substituted benzylamino-3(2H)-pyridazinone derivatives and their use as an anti-SRS-A agent, which are relatively similar to the compound of the present invention.

DISCLOSURE OF THE INVENTION

As the result of the extensive study, the present inventors have discovered that the 3(2H)-pyridazinone derivatives and their pharmaceutically acceptable salts of the present invention, which are different from any of the compounds disclosed in the above references (a)-(c), are excellent compounds for anti-thrombotic agents, cardiotonic agents, vasodilators and/or anti-SRS-A agents, and that they can be active ingredients of prophylactic or therapeutic drugs for the above-mentioned various thrombotic diseases, congestive heart failure, hypertension and/or asthma or immediate type allergy diseases. On the basis of this discovery, the present invention has been accomplished.

That is, the present invention relates to a 3(2H)-pyridazinone derivative and its pharmaceutically acceptable salt, a process for producing the same and a pharmaceutical composition containing the same as an active ingredient, the 3(2H)-pyridazinone derivative being represented by the general formula [I], ##STR2## {wherein R¹ is a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₄ alkenyl group or (CH₂)_(n) CO₂ R⁵ (n is an integer of from 1 to 4, R⁵ is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group);

R² is A¹ -Y¹ [A¹ is a straight chained or branched C₁ -C₁₂ alkylene group, Y¹ is CO₂ R⁵ (R⁵ is as defined above), a cyano group, OR⁶ (R⁶ is a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group or a phenyl group), or a thienyl or pyridyl group which may be substituted at any position, ##STR3## (R⁷ and R⁸ are respectively and independently a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group, a phenyl group or a thiazolyl or thiadiazolyl group which may be substituted at any position, or R⁷ and R⁸ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained or branched C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom), ##STR4## R⁵ is as defined above, R⁹ is a straight chained or branched C₁ -C₄ alkyl group or a phenyl group which may be substituted with a straight chained or branched C₁ -C₄ alkyl group or a halogen atom), ##STR5## (R¹⁰ and R¹¹ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₁ -C₄ acylamino group, OR⁵ (R⁵ is as defined above), NHSO₂ R⁹ (R⁹ is as defined above) or S(O)_(m) --R¹² (m is an integer of from 0 to 2 and R¹² is a straight chained or branched C₁ -C₄ alkyl group), provided that R¹⁰ and R¹¹ are not hydrogen atoms at the same time), ##STR6## (R¹³ is a hydrogen atom, R¹⁴ is a phenyl group, or R¹³ and R¹⁴ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group), ##STR7## (R¹⁵ is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group, R¹⁶ is a straight chained or branched C₁ -C₄ alkyl group, or R¹⁵ and R¹⁶ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group), ##STR8## (R¹⁷ and R¹⁸ are respectively and independently a straight chained or branched C₁ -C₄ alkyl group, or R¹⁷ and R¹⁸ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group), ##STR9## (1 is 1 or 2, x is an integer of from 0 to 3, and R¹⁹ is a hydrogen atom or a halogen atom), or ##STR10## ]; or R² is A² -Y² (A² is a C₂ -C₁₀ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon, and Y² is a phenyl group);

R³ and R⁴ are respectively and independently a hydrogen atom or a straight chained or branched C₁ -C₃ alkyl group;

X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; and

Ar is ##STR11## [j is 0 or 1 and R²⁰ is a hydrogen atom, a halogen atom or OR¹² (R¹² is as defined above)], ##STR12## (Z¹ is an oxygen atom or a sulfur atom), ##STR13## [R²¹ is a hydrogen atom or OR⁵ (R⁵ is as defined above)], or ##STR14## [Z² and Z³ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, OR²² (R²² is a hydrogen atom or a straight chained or branched C₁ -C₈ alkyl group), or O--A¹ --Y³ (A¹ is as defined above and Y³ is a phenyl group which may be substituted with a straight chained or branched C₁ -C₄ alkyl group or a halogen atom, CO₂ R⁵, or ##STR15## (R⁵, R⁷ and R⁸ are as defined above)), or Z² and Z³ together with a benzene ring, form ##STR16## (W forms a C₁ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group)]}; and a pharmaceutically acceptable salt thereof.

R¹, R², R³, R⁴, X and Ar in the above general formula [I] representing the compound of the present invention are explained hereinafter.

Examples of R¹ include, a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a 2-propenyl group, a 2-methyl-2-propenyl group, a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxylbutyl group, a methoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 3-methoxycarbonylpropyl group, a 4-methoxycarbonyl butyl group, an ethoxycarbonylmethyl group, a 2-ethoxycarbonylethyl group, a 3-ethoxycarbonylpropyl group, a 4-ethoxycarbonylbutyl group, an n-propoxycarbonylmethyl group, an i-propoxycarbonylmethyl group, a 2-n-propoxycarbonylethyl, a 2-i-propoxycarbonylethyl group, a 3-n-propoxycarbonylpropyl group, a 3-i-propoxycarbonylpropyl group, a 4-n-propoxycarbonylbutyl group, a 4-i-propoxycarbonylbutyl group, an n-butoxycarbonylmethyl group, an -i-butoxycarbonylmethyl group, a sec-butoxycarbonylmethyl group, a t-butoxycarbonylmethyl group, a 2-n-butoxycarbonylethyl group, a 2-i-butoxycarbonylethyl group, a 2-sec-butoxycarbonylethyl group, a 2-t-butoxycarbonylethyl group, a 3-n-butoxycarbonylpropyl group, a 3-i-butoxycarbonylpropyl group, a 3-sec-butoxycarbonylpropyl group, a 3-t-butoxycarbonylpropyl group, a 4-n-butoxycarbonylbutyl group, a 4-i-butoxycarbonylbutyl group, a 4-sec-butoxycarbonylbutyl group, a 4-t-butoxycarbonylbutyl group and the like, preferably a hydrogen atom, an ethyl group and an i-propyl group, and more preferably a hydrogen atom.

Examples of R² include A¹ -Y¹ or A² -Y² wherein A¹ is a straight chained or branched C₁ -C₁₂ alkylene group and A² is a C₂ -C₁₀ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon atom.

Examples of Y¹ include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a cyano group, a hydroxyl group, a methoxy group, an ethoxy group, an n-propoxy group-, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, a phenoxy group, a carbamoyl group, an N-methylaminocarbonyl group, an N-ethylaminocarbonyl group, an N-n-propylaminocarbonyl group, an N-i-propylaminocarbonyl group, an N-n-butylaminocarbonyl group, an N-i-butylaminocarbonyl group, an N-sec-butylaminocarbonyl group, an N-t-butylaminocarbonyl group, an N-cyclopropylaminocarbonyl group, an N-cyclobutylaminocarbonyl group, an N-cyclopentylaminocarbonyl group, an N-cyclohexylaminocarbonyl group, an N-cycloheptylaminocarbonyl group, an N-cyclooctylaminocarbonyl group, an N-phenylaminocarbonyl group, an N-2-thiazolylaminocarbonyl group, an N-4-thiazolylaminocarbonyl group, an N-5-thiazolylaminocarbonyl group, an N-2-thiadiazolylaminocarbonyl group, an N-5-thiadiazolylaminocarbonyl group, a 1-aziridinocarbonyl group, a 1-azetidinocarbonyl group, a 1-pyrrolidinocarbonyl group, a 1-piperidinocarbonyl group, a 1-homopiperidinocarbonyl group, a 1-(2,5-dimethyl)pyrrolidinocarbonyl group, a 1-(2,6-dimethyl)piperidinocarbonyl group, a 1-(3-phenyl)pyrrolidinocarbonyl group, a 1-(4-phenyl)piperidinocarbonyl group, an N-methylsulfonylamino group, an N-ethylsulfonylamino group, an N-n-propylsulfonyl group, an N-i-propylsulfonylamino group, an N-n-butylsulfonylamino group, an N-i-butylsulfonylamino group, an N-sec-butylsulfonylamino group, an N-t-butylsulfonylamino group, a 1-morpholinocarbonyl group, an N-phenylsulfonylamino group, an N-substituted phenylsulfonylamino group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a substituted phenyl group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a methylsulfonylamino group, an ethylsulfonylamino group, an N-n-propylsulfonylamino group, an N-i-propylsulfonylamino group, an N-n-butylsulfonylamino group, an N-i-butylsulfonylamino group, an N-sec-butylsulfonylamino group, an N-t-butylsulfonylamino group, an N-phenylsulfonylamino group, a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, an N-substituted phenylsulfonylamino group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, a sec-butylthio group, a t-butylthio group, a methylsulfoxy group, an ethylsulfoxy group, an n-propylsulfoxy group, an i-propylsulfoxy group, an n-butylsulfoxy group, an i-butylsulfoxy group, a sec-butylsulfoxy group, a t-butylsulfoxy group, a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i-butylsulfonyl group, a sec-butylsulfonyl group, or a t-butylsulfonyl group on the ortho-, meta- or para-position of the benzene ring), an N-phenylcarbonylamino group, a 1-(2-oxo)azetidinyl group, a 1-(2-oxo)pyrrolidinyl group, a 1-(2-oxo)piperidinyl group, a 1-(2-oxo)homopiperidinyl group, a 1-(2-oxo-3,3-dimethyl)pyrrolidinyl group, a 1-(2-oxo-5,5-dimethyl)pyrrolidinyl group, an N-methoxycarbonylamino group, an N-ethoxycarbonylamino group, an N-n-propoxycarbonylamino group, an N-i-propoxycarbonylamino group, an N-n-butoxycarbonylamino group, an N-i-butoxycarbonylamino group, an N-sec-butoxycarbonylamno group, an N-t-butoxycarbonylamino group, a 3-(2-oxo)oxazolidinyl group, a 3-(2-oxo-5,5-dimethyl)oxazolidinyl group, a 3-(2-oxo-4,4-diethyl)oxazolidinyl group, a 3-(2-oxo-5,5-diethyl)oxazolidinyl group, an N,N-di-substituted amino group (having an optional combination of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group and a t-butyl group), a 1-azetidino group, a 1-pyrrolidino group, a 1-piperidino group, a 1-(2,5-dimethyl)pyrrolidino group, a 1-(3,4-dimethyl)pyrrolidino group, a 1-(4,4-dimethyl)piperidino group, a 1-(4-phenylmethyl)piperadino group, 1-(4-diphenylmethyl)piperadino group, a 1-(4-substituted phenylmethyl)piperadinyl or 1-(4-di-substituted phenylmethyl)piperadinyl group (which is substituted with a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a phenylaminocarboxyl group, an N,N-di-substituted aminocarbonyl group (having an optional combination of a linear or cyclic alkyl group, a phenyl group, a thiazolyl group or a thiadiazolyl group on the above described N-substituted aminocarbonyl groups), N-alkyl-N-phenylsulfonylamino, N,N-dialkylsulfonylamino or N-alkyl-N-alkoxycarbonylamino groups (having a linear or branched C₁ -C₄ alkyl substituent on the nitrogen atom of the above described N-phenylsulfonylamino, N-alkylsulfonylamino or N-alkoxycarbonylamino groups), di-substituted phenyl groups (which are substituted on the ortho-, meta- or para-position of the benzene ring with an optional combination of a halogen atom, a linear alkyl group, an acylamino group, a hydroxy group, an alkoxy group, an N-phenylsulfonylamino group, an N-alkylsulfonylamino group, a linear alkylthio group and a linear alkylsulfonyl group on the above described substituted phenyl groups), and the like.

Examples of Y² include a phenyl group.

Examples of R³ and R⁴ include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an i-propyl group, preferably a hydrogen atom.

Examples of X include a hydrogen atom, a chlorine atom, a bromine atom and a cyano group, preferably each substituent other than a hydrogen atom.

Examples of Ar include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a substituted 2-pyridyl group, 3-pyridyl or 4-pyridyl (which is substituted with a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group on the 2-, 3-, 4-, 5- or 6-position of the pyridine ring), an N-oxidopyrizyl group corresponding to the above described pyridyl or substituted pyridyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-naphthyl or 2-naphthyl group (which is substituted with a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group on an optional position of the naphthalene ring) or substituted phenyl groups having the following one or two substituents in optional combination at an optional position. Examples of the substituents include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a hydroxy group, an alkoxy group (having a linear or branched C₁ -C₈ alkyl group), a dioxyemthylene, 1,2-dioxyethylene or 1,3-dioxypropylene group (which comprises adjacent two substituents joined together), or an O--A¹ --Y³ group. A¹ is a linear or branched C₁ -C₁₀ alkylene group, Y³ is a phenyl group, a substituted phenyl group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), or the above-mentioned (with regard to Y¹) carboxyl, alkoxycarbonyl, 1-cycloaminocarbonyl, 1-morpholinocarbonyl, or carbamoyl, N-substituted or N,N-disubstituted aminocarbonyl group (having on a nitrogen atom an optional combination of two substituents of a hydrogen atom, a linear, branched or cyclic alkyl group, a phenyl group, a thiazolyl group and a thiadiazolyl group). Preferable examples include a 3-pyridyl group or 3-substituted-4-methoxyphenyl type group, but the present invention should not be limited to these examples.

In the above description "n", "i", "sec" and "t" respectively stand for "normal", "iso", "secondary" and "tertiary".

Preferable compounds of the compounds having the general formula [I] of the present invention are represented by the following general formula [IC], ##STR17## {wherein R^(1c) is a hydrogen atom;

R^(2') is A¹ -Y^(3') [A¹ is a straight Chained or branched C₁ -C₁₂ alkylene group, Y³ is CO₂ R^(5') (R^(5') is a straight chained or branched C₁₋₄ alkyl group), ##STR18## (R^(7') and R^(8') are respectively and independently a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group or a phenyl group, R^(7') and R^(8') together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom), ##STR19## (R⁵ is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group, R^(9') is a phenyl group which may be substituted with a straight chained or branched C₁ -C₄ alkyl group or a halogen atom), ##STR20## (R^(10') and R^(11') are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₁ -C₄ acylamino group, OR⁵ (R⁵ is as defined above), NHSO₂ R^(9") (R^(9") is a straight chained or branched C₁ -C₄ alkyl group) or S(O)_(m) --R¹² (m is 0 or 2 and R¹² is a straight chained or branched C₁ -C₄ alkyl group), provided that R^(10') and R^(11') are not hydrogen atoms at the same time), ##STR21## (R^(13') is a hydrogen atom, R^(14') is a phenyl group, or R^(13') and R^(14') together form a C₂ -C₅ alkylene group), ##STR22## (R^(15') is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group, R^(16') is a straight chained or branched C₁ -C₄ alkyl group, or R^(15') and R^(16') together form a C₂ -C₆ alkylene group), ##STR23## (R^(17') and R^(18') are respectively and independently a straight chained Or branched C₁ -C₄ alkyl group, or R^(17') and R^(18') together form a C₂ -C₆ alkylene group), ##STR24## (l is 1 or 2, and R¹⁹ is a hydrogen atom or a halogen atom), or ##STR25## ]; or R² is A² -Y² (A² is a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon, and Y² is a phenyl group);

Xc' is a chlorine atom, a bromine atom, or a cyano group; and

Ar' is a 3-pyridyl group, or ##STR26## [Z¹ is a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, OR²² (R²² is a hydrogen atom or a straight chained or branched C₁₋₈ alkyl group) or O--A³ --Y³ (A³ is a C₁ -C₄ alkylene group, Y³ is a phenyl group, CO₂ R^(5'), ##STR27## (R^(5'), R^(7') and R^(8') are as defined above))]}.

The compounds of the general formula [I] of the present invention include optical isomers and stereoisomers based on from 1 to 6 asymmetric carbon atoms.

Hereinafter, typical compounds of the 3(2H)-pyridazinone derivatives of the general formula [I] and pharmaceutically acceptable salts thereof of the present invention are illustrated in the following Table 1, but the present invention should not be limited thereto.

In Table 1, "n" stands for normal, "i" stands for iso, "sec" stands for secondary, "Me" stands for a methyl group, "Et" stands for an ethyl group, "Pr" stands for a propyl group, "Bu" stands for a butyl group, "Pen" stands for a pentyl group, "Hex" stands for a hexyl group, "Hep" stands for a heptyl group, "Oct" stands for an octyl group, "Ac" stands for an acetyl group, and "Ph" stands for a phenyl group.

Q1-Q108 in Table I are groups represented by the following formulas. ##STR28##

                                      TABLE I                                      __________________________________________________________________________     No.                                                                               R.sup.1                                                                              R.sup.2        R.sup.3                                                                           R.sup.4                                                                           X  Ar                                            __________________________________________________________________________      1 H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                  H  H  Cl Q23                                            2 H     (CH.sub.2).sub.5 CO.sub.2 H                                                                   H  H  Cl Q23                                            3 H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                  H  H  Cl Q76                                            4 H     (CH.sub.2).sub.5 CO.sub.2 H                                                                   H  H  Cl Q76                                            5 H     CH.sub.2 CO.sub.2 Et                                                                          H  H  Cl Q76                                            6 H     CH.sub.2 CO.sub.2 H                                                                           H  H  Cl Q76                                            7 H     CH.sub.2 CO.sub.2 Me                                                                          H  H  Cl Q76.HCl                                        8 H     (CH.sub.2).sub.5 CONHMe                                                                       H  H  Cl Q23                                            9 H     (CH.sub.2).sub.5 CONMe.sub.2                                                                  H  H  Cl Q23                                            10                                                                               H     (CH.sub.2).sub.5 CONH.sub.2                                                                   H  H  Cl Q23                                            11                                                                               H     (CH.sub.2).sub.5 CO-Q87                                                                       H  H  Cl Q23                                            12                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                  H  H  Cl Q23                                            13                                                                               H     (CH.sub.2).sub.5 CON(Me)-Q1                                                                   H  H  Cl Q23                                            14                                                                               H     (CH.sub.2).sub.3 CO.sub.2 Et                                                                  H  H  Cl Q23                                            15                                                                               H     (CH.sub.2).sub.3 CO.sub.2 H                                                                   H  H  Cl Q23                                            16                                                                               H     (CH.sub.2).sub.3 CONMe.sub.2                                                                  H  H  Cl Q23                                            17                                                                               H     (CH.sub.2).sub.3 CONEt.sub.2                                                                  H  H  Cl Q23                                            18                                                                               H     (CH.sub.2).sub.3 CO-Q87                                                                       H  H  Cl Q23                                            19                                                                               H     CH.sub.2 CO.sub.2 Et                                                                          H  H  Cl Q23                                            20                                                                               H     CH.sub.2 CO.sub.2 H                                                                           H  H  Cl Q23                                            21                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 -Q2                                                               H  H  Cl Q23                                            22                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 -Q2                                                               H  H  Cl Q76                                            23                                                                               H     (CH.sub.2).sub.2 NHSO.sub.2 Ph                                                                H  H  Cl Q23                                            24                                                                               H     (CH.sub.2).sub.2 NHSO.sub.2 Ph                                                                H  H  Cl Q76                                            25                                                                               H     (CH.sub.2).sub.5 CON-n-Pr.sub.2                                                               H  H  Cl Q23                                             26                                                                              H     (CH.sub.2).sub.5 CO-Q83                                                                       H  H  Cl Q23                                            27                                                                               H     (CH.sub.2).sub.5 CO-Q82                                                                       H  H  Cl Q23                                            28                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                  H  H  Cl Q76                                            29                                                                               H     (CH.sub.2).sub.5 CONMe.sub.2                                                                  H  H  Cl Q76                                            30                                                                               H     (CH.sub.2).sub.7 CO.sub.2 Me                                                                  H  H  Cl Q23                                            31                                                                               H     (CH.sub.2).sub.7 CO.sub.2 H                                                                   H  H  Cl Q23                                            32                                                                               H     (CH.sub.2).sub.5 CO-Q82                                                                       H  H  Cl Q76                                            33                                                                               H     (CH.sub.2).sub.5 CO-Q83                                                                       H  H  Cl Q76                                            34                                                                               H     (CH.sub.2).sub.7 CONMe.sub.2                                                                  H  H  Cl Q23                                            35                                                                               H     (CH.sub.2).sub.7 CONEt.sub.2                                                                  H  H  Cl Q23                                            36                                                                               H     (CH.sub.2).sub.7 CON-n-Pr.sub.2                                                               H  H  Cl Q23                                            37                                                                               H     (CH.sub.2).sub.7 CO-Q82                                                                       H  H  Cl Q23                                            38                                                                               H     (CH.sub.2).sub.7 CO-Q83                                                                       H  H  Cl Q23                                            39                                                                               H     (CH.sub.2).sub.7 CO-Q87                                                                       H  H  Cl Q23                                            40                                                                               H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                  H  H  Cl Q16                                            41                                                                               H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                  H  H  Br Q23                                            42                                                                               H     (CH.sub.2).sub.5 CO.sub.2 H                                                                   H  H  Br Q23                                            43                                                                               H     (CH.sub.2).sub.5 CONMe.sub.2                                                                  H  H  Br Q23                                            44                                                                               H     (CH.sub.2).sub.5 -Q82                                                                         H  H  Br Q23                                            45                                                                               H     (CH.sub.2).sub.5 -Q83                                                                         H  H  Br Q23                                            46                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                  H  H  Br Q23                                            47                                                                               H     (CH.sub.2).sub.5 CON-n-Pr.sub.2                                                               H  H  Br Q23                                            48                                                                               H     (CH.sub.2).sub.5 CO-Q87                                                                       H  H  Br Q23                                            49                                                                               H     (CH.sub.2).sub.5 CO.sub.2 H                                                                   H  H  Cl Q16                                            50                                                                               H     (CH.sub.2).sub.3 CO-Q83                                                                       H  H  Cl Q23                                            51                                                                               H     (CH.sub.2).sub.7 CO-Q83                                                                       H  H  Cl Q76                                            52                                                                               H     (CH.sub.2).sub.7 CO-Q83                                                                       H  H  Cl Q76.HCl                                        53                                                                               H     (CH.sub.2).sub.5 CONMe.sub.2                                                                  H  H  Cl Q16                                            54                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                  H  H  Cl Q16                                            55                                                                               H     (CH.sub.2).sub.5 CON-n-Pr.sub.2                                                               H  H  Cl Q16                                            56                                                                               H     (CH.sub.2).sub.5 CO-Q82                                                                       H  H  Cl Q16                                            57                                                                               H     (CH.sub.2).sub. 5 CO-Q83                                                                      H  H  Cl Q16                                            58                                                                               H     (CH.sub.2).sub.5 CO-Q87                                                                       H  H  Cl Q16                                            59                                                                               H     (CH.sub.2).sub.7 CO.sub.2 Me                                                                  H  H  Br Q23                                            60                                                                               H     (CH.sub.2).sub.3 CO-Q84                                                                       H  H  Cl Q23                                            61                                                                               H     (CH.sub.2).sub.5 CO-Q84                                                                       H  H  Cl Q23                                            62                                                                               H     (CH.sub.2).sub.7 CO-Q84                                                                       H  H  Cl Q23                                            63                                                                               H     (CH.sub.2).sub.7 CONMe.sub.2                                                                  H  H  Br Q23                                            64                                                                               H     (CH.sub.2).sub.7 CONEt.sub.2                                                                  H  H  Br Q23                                            65                                                                               H     (CH.sub.2).sub.7 CON-n-Pr.sub.2                                                               H  H  Br Q23                                            66                                                                               H     (CH.sub.2).sub.7 CO-Q82                                                                       H  H  Br Q23                                            67                                                                               H     (CH.sub.2).sub.7 CO-Q83                                                                       H  H  Br Q23                                            68                                                                               H     (CH.sub.2).sub.7 CO-Q87                                                                       H  H  Br Q23                                            69                                                                               H     (CH.sub.2).sub.4 CO-Q83                                                                       H  H  Cl Q76                                            70                                                                               H     (CH.sub.2).sub.4 CO-Q83                                                                       H  H  Br Q76                                            71                                                                               H     (CH.sub.2).sub.4 CO-Q83                                                                       H  H  Cl Q23                                            72                                                                               H     (CH.sub.2).sub.5 CO-Q83                                                                       H  H  Cl Q76.HCl                                        73                                                                               H     (CH.sub.2).sub.5 CO-Q83                                                                       H  H  Cl Q76.Q105                                       74                                                                               H     (CH.sub.2).sub.5 CO-Q85                                                                       H  H  Cl Q76                                            75                                                                               H     (CH.sub.2).sub.5 CO-Q85                                                                       H  H  Cl Q76.HCl                                        76                                                                               H     (CH.sub.2).sub.5 CO-Q85                                                                       H  H  Cl Q76.Q105                                       77                                                                               H     (CH.sub.2).sub.3 CO-Q85                                                                       H  H  Cl Q76                                            78                                                                               H     (CH.sub.2).sub.3 CO-Q83                                                                       H  H  Cl Q76.HCl                                        79                                                                               H     (CH.sub.2).sub.3 CO-Q85                                                                       H  H  Cl Q76.HCl                                        80                                                                               H     (CH.sub.2).sub.2 Ph                                                                           H  H  Br Q76.HCl                                        81                                                                               H     (CH.sub.2).sub.4 CO-Q83                                                                       H  H  Cl Q76.HCl                                        82                                                                               H     (CH.sub.2).sub.4 CO-Q83                                                                       H  H  Br Q76.HCl                                        83                                                                               H     (CH.sub.2).sub.2 Ph                                                                           H  H  Br Q23                                            84                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Br Q23                                            85                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Br Q76.HCl                                        86                                                                               H     (CH.sub.2).sub.5 CO-Q95                                                                       H  H  Cl Q23                                            87                                                                               H     (CH.sub.2).sub.7 CO-Q95                                                                       H  H  Cl Q23                                            88                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Br Q58                                            89                                                                               H     (CH.sub.2).sub.5 CO.sub.2 H                                                                   H  H  Br Q76                                            90                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Cl Q23                                            91                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Cl Q76                                            92                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Cl Q76.HCl                                        93                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Cl Q76.Q105                                       94                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Br Q61                                            95                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                H  H  Cl Q76                                            96                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                H  H  Br Q23                                            97                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                H  H  Br Q76                                            98                                                                               H     (CH.sub.2).sub.6 NHSO.sub.2 Ph                                                                H  H  Br Q23                                            99                                                                               H     (CH.sub.2).sub.6 NHSO.sub.2 Ph                                                                H  H  Br Q76                                           100                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                H  H  Cl Q23                                           101                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Br Q76                                           102                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q76                                           103                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q23                                           104                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q76                                           105                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Cl Q76                                           106                                                                               H     (CH.sub.2).sub. 3 -Q2                                                                         H  H  Br Q76                                           107                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  CN Q76                                           108                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  Br Q76                                           109                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  Br Q23                                           110                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  Br Q28                                           111                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  Br Q76                                           112                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  Br Q23                                           113                                                                               H     (CH.sub.2).sub.5 CONHPh                                                                       H  H  Br Q76.HCl                                       114                                                                               H     (CH.sub.2).sub.3 CONHPh                                                                       H  H  Br Q76                                           115                                                                               H     (CH.sub.2).sub.3 CONH-Q96                                                                     H  H  Br Q23                                           116                                                                               H     (CH.sub.2).sub.3 CONH-Q97                                                                     H  H  Br Q23                                           117                                                                               H     (CH.sub.2).sub.5 CONH-Q97                                                                     H  H  Br Q23                                           118                                                                               H     (CH.sub.2).sub.3 CONEt.sub.2                                                                  H  H  Br Q76                                           119                                                                               H     (CH.sub.2).sub.5 CON(Me)-Q1                                                                   H  H  Br Q76                                           120                                                                               H     (CH.sub.2).sub.3 CON(Me)-Q1                                                                   H  H  Br Q23                                           121                                                                               H     (CH.sub.2).sub.5 CON(Me)-Ph                                                                   H  H  Br Q76.HCl                                       122                                                                               H     (CH.sub.2).sub.3 CON(ME)-Ph                                                                   H  H  Br Q76                                           123                                                                               H     (CH.sub.2).sub.5 CON(Et)-Ph                                                                   H  H  Br Q76.HCl                                       124                                                                               H     (CH.sub.2).sub.3 CON(Et)-Ph                                                                   H  H  Br Q76                                           125                                                                               H     (CH.sub.2).sub.5 CON(Et)-Ph                                                                   H  H  Br Q23                                           126                                                                               H     (CH.sub.2).sub.5 CO-Q87                                                                       H  H  Br Q76.HCl                                       127                                                                               H     (CH.sub.2).sub.3 CO-Q87                                                                       H  H  Br Q76                                           128                                                                               H     (CH.sub.2).sub.5 CO-Q86                                                                       H  H  Cl Q23                                           129                                                                               H     (CH.sub.2).sub.4 NHCOPh                                                                       H  H  Br Q76                                           130                                                                               H     (CH.sub.2).sub.4 NHCOPh                                                                       H  H  Br Q23                                           131                                                                               H     (CH.sub.2).sub.6 -Q88                                                                         H  H  Br Q76                                           132                                                                               H     (CH.sub.2).sub.5 -Q88                                                                         H  H  Br Q76                                           133                                                                               H     (CH.sub.2).sub.6 -Q88                                                                         H  H  Br Q23                                           134                                                                               H     (CH.sub.2).sub.6 -Q90                                                                         H  H  Br Q76                                           135                                                                               H     (CH.sub.2).sub.5 -Q90                                                                         H  H  Br Q76.HCl                                       136                                                                               H     (CH.sub.2).sub.5 NHSO.sub.2 Me                                                                H  H  Br Q76                                           137                                                                               H     (CH.sub.2).sub.5 -Q90                                                                         H  H  Br Q23                                           138                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 Me                                                                H  H  Br Q76                                           139                                                                               H     (CH.sub.2).sub.5 NHSO.sub.2 Me                                                                H  H  Br Q23                                           140                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 Me                                                                H  H  Br Q23                                           141                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Br Q76                                           142                                                                               H     (CH.sub.2).sub.4 N(Me)SO.sub.2 Ph                                                             H  H  Br Q76                                           143                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Br Q23                                           144                                                                               H     (CH.sub.2).sub.4 N(Me)SO.sub.2 Ph                                                             H  H  Br Q23                                           145                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Me                                                             H  H  Br Q76                                           146                                                                               H     (CH.sub.2).sub.5 N(Me)SO.sub.2 Me                                                             H  H  Br Q76                                           147                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Me                                                             H  H  Br Q23                                           148                                                                               H     (CH.sub.2).sub.5 N(Me)SO.sub.2 Me                                                             H  H  Br Q23                                           149                                                                               H     (CH.sub.2).sub.4 NHCO.sub.2 Me                                                                H  H  Br Q76                                           150                                                                               H     (CH.sub.2).sub.5 NHCO.sub.2 Me                                                                H  H  Br Q76                                           151                                                                               H     (CH.sub.2).sub.3 NHCO.sub.2 Me                                                                H  H  Br Q76                                           152                                                                               H     (CH.sub.2).sub.4 NHCO.sub.2 Me                                                                H  H  Br Q23                                           153                                                                               H     (CH.sub.2).sub.5 NHCO.sub.2 Me                                                                H  H  Br Q23                                           154                                                                               H     (CH.sub.2).sub.4 N(Me)CO.sub.2 Me                                                             H  H  Br Q76                                           155                                                                               H     (CH.sub.2).sub.5 N(Me)CO.sub.2 Me                                                             H  H  Br Q76                                           156                                                                               H     (CH.sub.2).sub.3 N(Me)CO.sub.2 Me                                                             H  H  Br Q76                                           157                                                                               H     (CH.sub. 2).sub.4 N(Me)CO.sub.2 Me                                                            H  H  Br Q23                                           158                                                                               H     (CH.sub.2).sub.5 N(Me)CO.sub.2 Me                                                             H  H  Br Q23                                           159                                                                               H     (CH.sub.2).sub.5 -Q89                                                                         H  H  Br Q76                                           160                                                                               H     (CH.sub.2).sub.6 -Q89                                                                         H  H  Br Q76                                           161                                                                               H     (CH.sub.2).sub.4 -Q89                                                                         H  H  Br Q76                                           162                                                                               H     (CH.sub.2).sub.6 -Q89                                                                         H  H  Br Q23                                           163                                                                               H     (CH.sub.2).sub.4 -Q89                                                                         H  H  Br Q23                                           164                                                                               H     (CH.sub.2).sub.4 OCONHPh                                                                      H  H  Br Q76.HCl                                       165                                                                               H     (CH.sub.2).sub.6 OCONHPh                                                                      H  H  Br Q76.HCl                                       166                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q76.HCl                                       167                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Cl Q76.HCl                                       168                                                                               H     (CH.sub.2).sub.4 -Q2                                                                          H  H  Cl Q76                                           169                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q76.Q104                                      170                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q76.Q107                                      171                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q76.Q106                                      172                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q76.Q108                                      173                                                                               H     (CH.sub.2).sub.3 -Q7                                                                          H  H  Br Q76                                           174                                                                               H     (CH.sub.2).sub.4 -Q7                                                                          H  H  Br Q76                                           175                                                                               H     (CH.sub.2).sub.5 -Q7                                                                          H  H  Br Q76                                           176                                                                               H     (CH.sub.2).sub.5 -Q7                                                                          H  H  Cl Q76                                           177                                                                               H     (CH.sub.2).sub.3 -Q7                                                                          H  H  Br Q23                                           178                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Br Q23                                           179                                                                               H     (CH.sub.2).sub.3 -Q12                                                                         H  H  Br Q76                                           180                                                                               H     (CH.sub.2).sub.3 -Q8                                                                          H  H  Br Q76                                           181                                                                               H     (CH.sub.2).sub.2 C(Me.sub.2)-Q2                                                               H  H  Br Q76.HCl                                       182                                                                               H     (CH.sub.2).sub.3 -Q23                                                                         H  H  Br Q76                                           183                                                                               H     (CH.sub.2).sub.3 -Q23                                                                         H  H  Br Q23                                           184                                                                               H     (CH.sub.2).sub.3 -Q25                                                                         H  H  Br Q76                                           185                                                                               H     (CH.sub.2).sub.3 -Q25                                                                         H  H  Br Q23                                           186                                                                               H     (CH.sub.2).sub.3 -Q26                                                                         H  H  Br Q76                                           187                                                                               H     (CH.sub.2).sub.3 -Q26                                                                         H  H  Br Q23                                           188                                                                               H     (CH.sub.2).sub.3 -Q15                                                                         H  H  Br Q76                                           189                                                                               H     (CH.sub.2).sub.3 -Q15                                                                         H  H  Br Q23                                           190                                                                               H     (CH.sub.2).sub.3 -Q13                                                                         H  H  Br Q76                                           191                                                                               H     (CH.sub.2).sub.3 -Q14                                                                         H  H  Br Q76                                           192                                                                               H     (CH.sub.2).sub.3 -Q75                                                                         H  H  Br Q23                                           193                                                                               H     (CH.sub.2).sub.3 -Q98                                                                         H  H  Br Q76.HCl                                       194                                                                               H     (CH.sub.2).sub.3 -Q99                                                                         H  H  Br Q76                                           195                                                                               H     (CH.sub.2).sub.3 -Q99                                                                         H  H  Br Q23                                           196                                                                               H     (CH.sub.2).sub.3 -Q76                                                                         H  H  Br Q76                                           197                                                                               H     (CH.sub.2).sub.3 -Q76                                                                         H  H  Br Q23                                           198                                                                               H     (CH.sub.2).sub.2 OPh                                                                          H  H  Br Q76                                           199                                                                               H     (CH.sub.2).sub.2 OPh                                                                          H  H  Br Q23                                           200                                                                               H     (CH.sub.2).sub.6 CN                                                                           H  H  Br Q76                                           201                                                                               H     (CH.sub.2).sub.6 CN                                                                           H  H  Br Q23                                           202                                                                               H     (CH.sub.2).sub.2 -Q82.HCl                                                                     H  H  Br Q23                                           203                                                                               H     (CH.sub.2).sub.3 NMe.sub.2.HCl                                                                H  H  Br Q23                                           204                                                                               H     (CH.sub.2).sub.2 NEt.sub.2.HCl                                                                H  H  Br Q23                                           205                                                                               H     (CH.sub.2).sub.3 -Q92.2HCl                                                                    H  H  Br Q23                                           206                                                                               H     (CH.sub.2).sub.3 -Q93.2HCl                                                                    H  H  Br Q23                                           207                                                                               H     (CH.sub.2).sub.3 -Q94.2HCl                                                                    H  H  Br Q23                                           208                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  Cl  Q101                                         209                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                  H  H  Cl  Q101                                         210                                                                               H     C(Me)H(CH.sub.2).sub.2 Ph                                                                     H  H  Br Q76.HCl                                       211                                                                               H     (CH.sub.2).sub.3 Ph                                                                           Me H  Cl  Q101                                         212                                                                               H     (CH.sub.2).sub.2 C(Me.sub.2)-Q2                                                               H  H  Br  Q101                                         213                                                                               H     (CH.sub.2).sub.3 -Q93.2HCl                                                                    H  H  Br  Q101                                         214                                                                               H     CH.sub.2 C(Me).sub.2 CH.sub.2 -Q2                                                             H  H  Cl Q76                                           215                                                                               H     C(Me)H(CH.sub.2).sub.2 Ph                                                                     H  H  Br  Q101                                         216                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Cl  Q101                                         217                                                                               Et    (CH.sub.2).sub.3 Ph                                                                           H  H  Cl  Q101                                         218                                                                               i-Pr  (CH.sub.2).sub.3 Ph                                                                           H  H  Cl  Q101                                         219                                                                               H     (CH.sub.2).sub.5 NHCO.sub.2 Me                                                                H  H  Br  Q101                                         220                                                                               H     C(Me)H(CH.sub.2).sub.2 -Q2                                                                    H  H  Br Q76                                           221                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q78                                           222                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q22                                           223                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br  Q100                                         224                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br  Q102                                         225                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Ph                                            226                                                                               Me    (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q23                                           227                                                                               CH.sub.2 CO.sub. 2 H                                                                 (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q23                                           228                                                                               H     (CH.sub.2).sub.3 -Ph                                                                          H  H  Br Q28                                           229                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q76                                           230                                                                               H     (CH.sub.2).sub.3 -Ph                                                                          H  H  Br Q77                                           231                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q24                                           232                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q27                                           233                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q28                                           234                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q23                                           235                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Br Q76                                           236                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br  Q103                                         237                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q79                                           238                                                                               CH.sub.2 CO.sub.2 Et                                                                 (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q23                                           239                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q23                                           240                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q46                                           241                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q76                                           242                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q21                                           243                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q23                                           244                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q24                                           245                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q28                                           246                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q30                                           247                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q48                                           248                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q49                                           249                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q68                                           250                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q69                                           251                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q70                                           252                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q71                                           253                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q72                                           254                                                                               H     (CH.sub.2).sub.3 Ph                                                                           H  H  CN Q73                                           255                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q76                                           256                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  CN Q76                                           257                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q21                                           258                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q23                                           259                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q28                                           260                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q16                                           261                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q17                                           262                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q35                                           263                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q36                                           264                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q71                                           265                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q41                                           266                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q43                                           267                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q44                                           268                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Br Q45                                           269                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q49                                           270                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q50                                           271                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q51                                           272                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q52                                           273                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q56                                           274                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q58                                           275                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q62                                           276                                                                               H     (CH.sub.2).sub.4 Ph                                                                           H  H  Cl Q63                                           277                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Cl Q76                                           278                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  CN Q76                                           279                                                                               Et    (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q76                                           280                                                                               Allyl (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q76                                           281                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q23                                           282                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q29                                           283                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q32                                           284                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q41                                           285                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q45                                           286                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q43                                           287                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q37                                           288                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q38                                           289                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q40                                           290                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q34                                           291                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q33                                           292                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q58                                           293                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q59                                           294                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q55                                           295                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q56                                           296                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q61                                           297                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q60                                           298                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q64                                           299                                                                               H     (CH.sub. 2).sub.3 -Q10                                                                        H  H  Br Q57                                           300                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q63                                           301                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q51                                           302                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q52                                           303                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q53                                           304                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q66                                           305                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q69                                           306                                                                               H     (CH.sub.2).sub.3 -Q10                                                                         H  H  Br Q74                                           307                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q76                                           308                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  Me Cl Q76                                           309                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         Me H  Br Q76                                           310                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  CN Q76                                           311                                                                               H     (CH.sub.2).sub.4 -Q11                                                                         H  H  Cl Q76                                           312                                                                               H     (CH.sub.2).sub.5 -Q11                                                                         H  H  Cl Q76                                           313                                                                               H     (CH.sub.2).sub.8 -Q11                                                                         H  H  Cl Q76                                           314                                                                               H     C(Me)H(CH.sub.2).sub.2 -Q11                                                                   H  H  Cl Q76                                           315                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q23                                           316                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q27                                           317                                                                               H     (CH.sub.2).sub. 3 -Q11                                                                        H  H  Cl Q28                                           318                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q31                                           319                                                                               H     (CH.sub.2).sub.5 -Q11                                                                         H  H  Cl Q23                                           320                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q19                                           321                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q45                                           322                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q43                                           323                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q38                                           324                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q39                                           325                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q42                                           326                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q48                                           327                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q62                                           328                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q54                                           329                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q58                                           330                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q59                                           331                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q61                                           332                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q50                                           333                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q51                                           334                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q52                                           335                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q65                                           336                                                                               H     (CH.sub.2).sub.3 -Q11                                                                         H  H  Cl Q67                                           337                                                                               H     (CH.sub.2).sub.3 -Q3                                                                          H  H  Cl Q76                                           338                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Cl Q23                                           339                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Cl Q28                                           340                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  Cl Q76                                           341                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  CN Q76                                           342                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  Cl Q76                                           343                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  CN Q76                                           344                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  CN Q28                                           345                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  Cl Q17                                           346                                                                               H     (CH.sub.2).sub.3 -Q88                                                                         H  H  Cl Q18                                           347                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  Cl Q23                                           348                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  Cl Q16                                           349                                                                               H     (CH.sub.2).sub.3 -Q90                                                                         H  H  Cl Q28                                           350                                                                               H     (CH.sub.2).sub.3 -Q91                                                                         H  H  Br Q76                                           351                                                                               H     (CH.sub.2).sub.3 -Q91                                                                         H  H  Br Q23                                           352                                                                               H     (CH.sub.2).sub.3 -Q91                                                                         H  H  Br Q19                                           353                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Cl Q76                                           354                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  Cl Q76                                           355                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q4                                                            H  H  Cl Q76                                           356                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  Br Q76                                           357                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  CN Q76                                           358                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Cl Q23                                           359                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  Cl Q23                                           360                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q6                                                            H  H  Cl Q23                                           361                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Cl Q24                                           362                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  Cl Q28                                           363                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Cl Q58                                           364                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                             H  H  Cl Q61                                           365                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Ph                                                             H  H  Br Q76                                           366                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 -Q2                                                            H  H  Br Q76                                           367                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 -Q5                                                            H  H  Br Q76                                           368                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  CN Q23                                           369                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q2                                                            H  H  CN Q28                                           370                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 -Q3                                                            H  H  CN Q23                                           371                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q80                                           372                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q81                                           373                                                                               H     C(Me.sub.2)(CH.sub.2).sub.2 -Q2                                                               H  H  Br Q76                                           374                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q2                                                              H  H  Br Q76                                           375                                                                               H     C(Et.sub.2)(CH.sub.2).sub.2 -Q2                                                               H  H  Br Q76                                           376                                                                               H     C(n-Pr.sub.2)(CH.sub.2).sub.2 -Q2                                                             H  H  Br Q76                                           377                                                                               H     C(Me.sub.2)CH.sub.2 C(Me.sub.2)-Q2                                                            H  H  Br Q76                                           378                                                                               H     CH.sub.2 C(Et.sub.2)CH.sub.2 -Q2                                                              H  H  Br Q76                                           379                                                                               H     CH.sub.2 C(n-Pr.sub.2)CH.sub.2 -Q2                                                            H  H  Br Q76                                           380                                                                               H     (CH.sub.2).sub.2 C(Et.sub.2)-Q2                                                               H  H  Br Q76                                           381                                                                               H     (CH.sub.2).sub.2 C(n-Pr.sub.2)-Q2                                                             H  H  Br Q76                                           382                                                                               H     C(Me.sub.2)(CH.sub.2).sub.3 -Q2                                                               H  H  Br Q76                                           383                                                                               H     CH.sub.2 C(Me.sub.2)(CH.sub.2).sub.2 -Q2                                                      H  H  Br Q76                                           384                                                                               H     (CH.sub.2).sub.2 C(Me.sub.2 )CH.sub.2 -Q2                                                     H  H  Br Q76                                           385                                                                               H     (CH.sub.2).sub.3 C(Me.sub.2)-Q2                                                               H  H  Br Q76                                           386                                                                               H     C(Me.sub.2)(CH.sub.2).sub.2 C(Me.sub.2)-Q2                                                    H  H  Br Q76                                           387                                                                               H     C(Me.sub.2)CH.sub.2 C(Me.sub.2)CH.sub.2 -Q2                                                   H  H  Br Q76                                           388                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 C(Me.sub.2)-Q2                                                   H  H  Br Q76                                           389                                                                               H     C(i-Pr.sub.2)(CH.sub.2).sub.2 -Q2                                                             H  H  Br Q76                                           390                                                                               H     CH.sub.2 C(i-Pr.sub.2)CH.sub.2 -Q2                                                            H  H  Br Q76                                           391                                                                               H     (CH.sub.2).sub.2 C(i-Pr.sub.2)-Q2                                                             H  H  Br Q76                                           392                                                                               H     (CH.sub.2).sub.3 -Q2                                                                          H  H  Br Q47                                           393                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Ph                                                               H  H  Br Q76                                           394                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CO.sub.2 H                                                       H  H  Br Q76                                           395                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CO.sub.2 Me                                                      H  H  Br Q76                                           396                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CN                                                               H  H  Br Q76                                           397                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 OH                                                               H  H  Br Q76                                           398                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 OMe                                                              H  H  Br Q76                                           399                                                                               H     CH.sub. 2 C(Me.sub.2)CH.sub.2 -Q98                                                            H  H  Br Q76                                           400                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q76                                                             H  H  Br Q76                                           401                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CONEt.sub.2                                                      H  H  Br Q76                                           402                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CO-Q83                                                           H  H  Br Q76                                           403                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CO-Q87                                                           H  H  Br Q76                                           404                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHSO.sub.2 Ph                                                    H  H  Br Q76                                           405                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHSO.sub.2 Me                                                    H  H  Br Q76                                           406                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 N(Me)SO.sub.2 Ph                                                 H  H  Br Q76                                           407                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 N(Me)SO.sub.2 Me                                                 H  H  Br Q76                                           408                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q7                                                              H  H  Br Q76                                           409                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q6                                                              H  H  Br Q76                                           410                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q10                                                             H  H  Br Q76                                           411                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q11                                                             H  H  Br Q76                                           412                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q8                                                              H  H  Br Q76                                           413                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q9                                                              H  H  Br Q76                                           414                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHCOPh                                                           H  H  Br Q76                                           415                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q90                                                             H  H  Br Q76                                           416                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHCO.sub.2 Me                                                    H  H  Br Q76                                           417                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 N(Me)CO.sub.2 Me                                                 H  H  Br Q76                                           418                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q89                                                             H  H  Br Q76                                           419                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -NEt.sub.2                                                       H  H  Br Q76                                           420                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q83                                                             H  H  Br Q76                                           421                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q92                                                             H  H  Br Q76                                           422                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -Q94                                                             H  H  Br Q76                                           423                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 -OCONHPh                                                         H  H  Br Q76                                           __________________________________________________________________________

A method for preparing the compounds of the present invention is explained hereinafter.

The 3(2H)-pyridazinone derivatives of the general formula [I] and pharmaceutically acceptable salts thereof of the present invention can be prepared by the following methods as illustrated by the reaction formulas (1)-(9). ##STR29## (wherein X¹ is a chlorine atom or a bromine atom, X² is a chlorine atom, a bromine atom or a hydrogen atom, and R¹, R², R³, R⁴ and Ar are as defined above.)

In the preparation method according to the reaction formula (1), a 4,5-dihalo- or 5-halo-3(2H)-pyridazinone compound of the formula [IIA] is reacted with an arylmethylamine derivative of the formula [III] or its salt optionally in the presence of a dehydrohalogenating agent in an inert solvent to produce a compound of the formula [IA] wherein the 4-position of the compounds of the present invention of the formula [I] is bonded with X².

In the above reaction formula (1), when X² in the formula [IIA] is a chlorine atom or a bromine atom, a position isomer of the compound of the formula [IA], i.e. a compound of the formula [VA], ##STR30## (wherein R¹, R², R³, R⁴, X¹ and Ar are as defined above) having an arylmethylamino group substituted at the 4-position, is formed as a by-product, but the production ratios of the compounds of the formulas [IA] and [VA] depend primarily upon the polarity of the solvent used.

Namely, when a solvent of high polarity is used, the production ratio of the compound [IA] of the present invention tends to be high. Conversely, when a solvent of low polarity (such as benzene, toluene or hexane) is used, the production ratio of the compound [VA] tends to be high.

Therefore, as a solvent suitable for suppressing by-production of the compound of the formula [VA] and for efficient production of the compounds [IA] of the present invention, an ether type solvent (such as tetrahydrofuran or 1,4-dioxane), an amide type solvent (such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone), acetonitrile, dimethylsulfoxide, an alcohol type solvent (such as methanol, ethanol or propanol), an organic amine solvent (such as pyridine, triethylamine, N,N-dimethylaminoethanol or triethanolamine), or water, or a solvent mixture thereof, may be mentioned.

The desired compound of the formula [IA] of the present invention can readily be separated and purified from the mixture of the compounds of the formulas [IA]and [VA] by conventional methods known per se in organic synthesis, such as fractional recrystallization or various silica gel chromatography.

When a compound of the formula [IIA] wherein X² is a hydrogen atom, i.e. 5-halo-3(2H)-pyridazinone, is used, benzene, toluene, xylene, n-hexane, n-heptane and the like may also be used as a reaction solvent in addition to the above-mentioned solvents.

During the reaction between the compound of the formula [IIA] and the compound of the formula [III], hydrogen chloride or hydrogen bromide is generated. It is usually possible to improve the yield by adding to the reaction system a dehydrohalogenating agent which traps such a hydrogen halide.

Any dehydrohalogenating agent may be used so long as it does not adversely affect the reaction and is capable of trapping a hydrogen halide. As such a dehydrohalogenating agent, an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate, or an organic base such as N,N-dimethylaniline, N,N-diethylaniline, trimethylamine, triethylamine, N,N-dimethylaminoethanol or pyridine, may be mentioned.

Otherwise, the starting material arylmethylamine derivative of the formula [III] may be used in an excessive amount as the dehydrohalogenating agent. This gives an improved yield in many cases.

The reaction temperature may be within a range of from 10° C. to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials may optionally be set. However, the arylmethylamine derivative of the formula [III] or its salt may be used usually in an amount of from 1 to 10 mols, preferably from 1.2 to 5 mols, relative to one mol of the 4,5-dihalo- or 5-halo-3(2H)-pyridazinone derivative of the formula [IIA].

The 4,5-dihalo or 5-halo-3(2H)-pyridazinone derivative of the formula [IIA] can be prepared by a conventional process or by application of a conventional organic reaction as described below.

Namely, the 4,5-dihalo- or 5-halo-3(2H)-pyridazinone derivative of the formula [IIA] can be prepared by the method disclosed in the above-mentioned reference (c).

Among the arylmethylamine derivatives of the formula [III] and their salts in Process (1), those not available as commercial products can be prepared by the method disclosed in Japanese Unexamined Patent Publication No. 267560/1986. (Corresponding U.S. Pat. No. 5,098,900 and European Patent No. 0.186,817). ##STR31## (wherein R¹, R², R¹, R⁴, X¹ and Ar are as defined above.)

The above reaction formula (2) illustrates a method for preparing a 4-cyano-5-arylmethylamino derivative of the formula [IB] of the present invention by halogen-substitution reaction between a 4-halo-5-arylmethylamino derivative of the formula [IB-a] and a metal cyanide of the formula [IV].

Examples of metal M include a lithium atom, a sodium atom, a potassium atom, a copper atom and the like.

As a reaction solvent, an amide type solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone etc., an alcohol solvent such as methanol, ethanol, n-propanol, n-butanol etc., dimethyl sulfoxide and their water-containing solvents are preferably used.

The reaction temperature varies depending upon the reactants used, but it is usually within a range of from room temperature to the boiling point of the solvent used for the reaction. Generally, the reaction of a bromine atom as a halogen atom at the 4-position proceeds under milder temperature conditions than the reaction of a chlorine atom.

The molar ratio of the starting materials can be optionally determined, and it is sufficient that the metal cyanide of the formula [IV] is used in an amount of from 1.2 to 10 mols relative to one mol of the 4-halo-5-arylmethylamino derivative of the formula [IB-a].

The desired compound can readily be isolated and purified by a method known in organic synthesis such as recrystallization, various silica gel chromatography or distillation. ##STR32## (wherein R^(1') is a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₄ alkenyl group or (CH₂)_(n) CO₂ R⁵, hal is a chlorine atom, a bromine atom, an iodione atom or other eliminatable functional groups, and n, R², R³, R⁴, R⁵, X and Ar are as defined above.)

The above reaction formula (3) illustrates a method for preparing in substitution product at the 2-position of the formula [I-b] of the present invention by reacting a compound of the formula [I-a] wherein the 2-position of the pyridazinone is occupied by a hydrogen atom, among the compounds of the formula [I] of the present invention, with a reactive derivative having an eliminatable group such as a halogeno derivative, an alkyl sulfonate derivative or a phenyl sulfonate derivative as expressed by the formula R^(1') -hal.

The present reaction can be generally conducted in the presence of an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydroxide etc., or an organic base such as triethylamine, tri-n-propylamine etc.

When R³ is an alkyl group in the compound of the formula [I-a], a metal hydride and an organometallic compound such as sodium hydride, n-butyl lithium etc. may be used in addition to the above inorganic bases.

As a reaction solvent, a ketone type solvent (acetone, methyl ethyl ketone, diethyl ketone etc.), an amide type solvent (formamide, N,N-dimethylformamide, N,N-dimethylacetamide etc.), an alcohol type solvent (methanol, ethanol etc.), water and a mixture thereof can be suitably used when an inorganic base or an organic base is used, and an ether type solvent can be suitably used when a metal hydride is used.

In the case of using the inorganic base or the organic base, the reaction temperature is usually within a range of from 0° C. to the boiling point of the solvent, and in the case of using the metal hydride or the organometallic compound, it is usually within a range of from -78° C. to 60° C.

The molar ratio of the starting materials may optionally be determined. However, it is sufficient that the reactive derivative of the formula R^(1') -hal is used in an amount of from 1 to 5 mols relative to one mol of the compound of the formula [I-a].

The desired compound can be isolated and purified in accordance with the method as described with respect to the reaction formula (2). ##STR33## (wherein R¹, R², R³, R⁴, X, Ar and hal are as defined above.)

The above reaction formula (4) illustrates a method for preparing a compound of the formula [I] of the present invention by reacting a 6-hydroxy-5-arylmethylamino derivative of the formula [IC-a] with a reactive derivative of the formula R² -hal. The 6-hydroxy-5-arylmethyl derivative of the formula [IC-a] used as the starting material in the present reaction can be prepared in accordance with the methods disclosed in the above-mentioned reference (c) and reaction formula (2).

With regard to the reaction conditions, it is possible to employ reaction conditions similar to those in the above reaction formula (3). ##STR34## (wherein M¹ is an alkali metal atom, R^(1") is a protective group, and R¹, R², R³, R⁴, X and Ar are as defined above.)

The above reaction formula (5) illustrates a method for preparing a 6-alkoxy-5-arylmethylamino derivative of the formula [I] or the formula [I-a] of the present invention by substitution reaction of the nitro group of a 6-nitro-5-arylmethylamino derivative of the formula [ID-a] or the formula [ID-b] with an alkali metal alkoxide of the formula [VI]. The 6-nitro derivative of the formula [ID-a] and [ID-b] used as the starting material in the present reaction can be prepared in accordance with the method disclosed in the above-mentioned reference (c).

Among the desired compounds, a compound having hydrogen at 2-position of pyridazinone, can be prepared by the direct route as shown in the reaction formula (5)-(i) wherein R¹ of the formula [ID-a] and [I] is hydrogen, or by a route as shown in the reaction formula (5)-(ii) which comprises converting the 6-nitro-5-arylmethylamino derivative of the formula [ID-b] protected at 2-position with R^(1") to a compound of the formula [ID-c] and then removing the protecting group R^(1"), to obtain the desired compound. The yield is usually better in the latter method in many cases.

As the protective group R^(1"), tetrahydropyranyl, tetrahydrofuranyl, 2-trimethylsilylethoxymethyl (Me₃ SiCH₂ CH₂ OCH₂ --), pivaloyloxymethyl(Me₃ C--CO₂ CH₂ --), benzyloxymethy ##STR35## hydroxymethyl, methoxymethyl (MeOCH₂ --) or CO₂ R wherein R is a lower alkyl group, is preferably used.

The removal of the protective group R^(1") can easily be conducted by a conventional method for the removal of such protective groups.

Here, the alkali metal of the formula M¹ includes lithium, sodium and potassium.

Therefore, an alkali metal alkoxide of the formula [VI] used as a nucleophilic agent includes a metal alkoxide as defined by the above M¹ and R²

There is no particular restriction as to the reaction solvent so long as it is inert to the reaction, and there are enumerated an amide type solvent (such as N-methylpyrrolidone, formamide, N,N-dimethylformamide or N,N-dimethylacetamide), an ether type solvent (such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane), a benzene type solvent (such as benzene, toluene or xylene), and a mixture thereof.

The reaction temperature varies depending upon the reactants used. It is usually within a range of from -15° C. to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials can be optionally determined, and it is sufficient that the alkali metal alkoxide of the formula [VI] is used in an amount of from 1.2 to 10 mols relative to one mol of the 6-nitro-5-arylmethylamino derivative of the formula [ID-a] or the formula [ID-b].

The desired compound can readily be isolated and purified by a method known in organic syntheses such as recrystallization, various silica gel chromatography or distillation. ##STR36## (wherein R¹, R², R³, R⁴, X¹ and Ar are as defined above.)

The above reaction formula (6) illustrates a method for preparing the compound of the formula [IE] of the present invention wherein the 4-position is occupied by hydrogen by reductively removing a halogen atom of the 4-halo derivative of the formula [IB-a].

As the reduction method, catalytic hydrogenation is generally used. As a catalyst, there are enumerated palladium, platinum oxide, Raney nickel and the like, and the reaction proceeds relatively smoothly under a hydrogen pressure of from 1 to 10 atms.

When R² contains an atom which becomes a catalyst poison, a preferable result is sometimes obtained by using a metal hydride such as tri-n-butyltin hydride or lithium aluminum hydride.

As a reaction solvent, a protonic solvent is used in the case of catalytic hydrogenating reaction, and an ether type solvent is generally used in the case of using a metal hydride.

The reaction temperature may usually be within a range of from -10° C. to 100° C., and the reaction usually proceeds smoothly. ##STR37## (wherein R¹, R³, R⁴, R⁵, R⁷, R⁸, A¹, X and Ar are as defined above.)

The above reaction formula (7) illustrates a method for preparing a 6-aminocarbonylalkyleneoxy derivative of the formula [IF-b] by subjecting a 6-ω-carboxyalkyleneoxy derivative or 6-ω-alkoxycarbonylalkyleneoxy derivative of the formula [IF-a] and an amine compound of the formula [VII] to condensation reaction including dehydration or dealcohol.

As a condensation process where R⁵ is a hydrogen atom, there can be used a condensation method known in peptide synthesis, for example, acid chloride method, mixed acid anhydride method, or a condensation method using a condensation agent such as di-cyclohexylcarbodiimide, carbonyldiimidazole or N-hydroxysuccinic acid imide, and a condensation method is selected depending on the reactivity of amines of the formula [VII]. As a reaction condition, conditions usually used may be employed.

Among amines of the formula [VII], in the reaction with a highly nucleophilic amines, the condensation reaction can proceed even by using esters wherein R⁵ is an alkyl group. In this case, the solvent is not specially limited and any solvent can be used so long as it does not adversely affect the reaction. In some cases, the reaction can proceed in the absence of a solvent. The reaction temperature is within a range from room temperature to 200° C., more usually from 50° to 150° C. ##STR38## wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸, X, Z² and A¹ are as defined above.)

The above reaction formula (8) illustrates a method for preparing an amide derivative of the formula [IG-b] by subjecting a 5-(ω-carboxyalkyleneoxy)phenylmethylamino derivative or 5-(ω-alkoxycarbonylalkyleneoxy)phenylmethylamino derivative of the formula [IG-a] and an amine compound of the formula [VII] to condensation reaction.

The present reaction can be carried out in the same manner as in the reaction formula (7). ##STR39## (wherein R¹, R², R³, R⁴, R²⁰ and X are as defined above.)

The above reaction formula (9) illustrates a method for preparing an N-oxypyridylmethylamino derivative of the formula [IH-b] by oxidizing a nitrogen atom on the pyridine ring of a 5-pyridylmethylamino derivative of the formula [IH-a]. Examples of an oxidizing agent include performic acid, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, t-butylhydroperoxide, aqueous hydrogen peroxide and the like.

As a reaction solvent, there are enumerated a halogen type solvent (carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane etc.), an ether type solvent (diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), a benzene type solvent (benzene, toluene etc.), an alcohol type solvent (methanol, ethanol, t-butanol etc.), acetic acid, formic acid and the like. In some cases, a transition metal complex may be added as a catalyst.

The reaction temperature may be usually within a range of from -20° C. to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials may optionally be set, but the oxidizing agent may be used usually in an amount of from 1 to 10 mols, preferably from 1.2 to 5 mols, relative to one mol of the 5-pyridylmethylamino derivative of the formula [IH-a].

The desired compound can readily be isolated and purified by a method known in organic synthesis such as recrystallization, various silica gel chromatography or distillation.

As the manner of administration of the 3(2H)-pyridazinones of the formula [I] or their pharmaceutically acceptable salts of the present invention, there may be mentioned a non-oral administration by injection (subcutaneous, intravenous, intramuscular or intraperitoneal injection), an ointment, a suppository or an aerosol, or an oral administration in the form of tablets, capsules, granules, pills, syrups, liquids, emulsions or suspension.

The above pharmacological composition contains a compound of the present invention in an amount of from about 0.1 to about 99.5% by weight, preferably from about 0.5 to 95% by weight, based on the total weight of the composition.

To the compound of the present invention or to the composition containing the compound of the present invention, other pharmacologically active compounds may be incorporated.

Further, the composition of the present invention may contain a plurality of compounds of the present invention.

The clinical dose of the compound of the present invention varies depending upon the age, the body weight, the sensitivity or the sympton, etc. of the patient. However, the effective daily dose is usually from 0.003 to 1.5 g, preferably from 0.01 to 0.6 g, for an adult.

However, if necessary, an amount outside the above range may be employed.

The compounds of the present invention may be formulated into various suitable formulations depending upon the manner of administration, in accordance with conventional methods commonly employed for the preparation of pharmaceutical formulations.

Namely, tablets, capsules, granules or pills for oral administration, may be prepared by using an excipient such as sugar, lactose, glucose, starch or mannitol; a binder such as syrups, gum arabic, gelatin, sorbitol, tragacanth gum, methyl cellulose or polyvinylpyrrolidone; a disintegrant such as starch, carboxymethyl cellulose or its calcium salts, crystal cellulose powder or polyethylene glycol; a gloss agent such as talc, magnesium or calcium stearate or silica; or a lubricant such as sodium laurate or glycerol.

The injections, solutions, emulsions, suspensions, syrups or aerosols, may be prepared by using a solvent for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, or polyethylene glycol; a surfactant such as a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene ether of hydrogenated castor oil or lecithin, a suspending agent such as a sodium salt of carboxymethyl cellulose, a cellulose derivative such as methyl cellulose, or a natural rubber such as tragacanth gum or gum arabic; or a preservative such as a paraoxy benzoic acid ester, benzalkonium chloride or a salt of sorbic acid.

Likewise, the suppositories may be prepared by using e.g. polyethylene glycol, lanolin or coconut butter.

BEST MODE FOR CARRYING OUT THE INVENTION Examples (Preparation Examples, Formulation Examples and Test Examples)

Now, the present invention will be described in detail with reference to Examples (including Preparation Examples, Formulation Examples and Test Examples). However, it should be understood that the present invention is by no means restricted by these specific Examples. In Preparation Examples or in Table II, the symbols "NMR", "IR" and "MS" indicate "nuclear magnetic resonance spectrum", "infrared spectrum" and "mass spectrometry", respectively. IR was measured by the potassium bromide disk method, and NMR was measured in heavy hydrogen chloroform, unless otherwise specified.

In the MS data in Table II, only the principal peaks or typical fragment peaks are given.

PREPARATION EXAMPLE 1 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) ##STR40##

A mixture comprising 4.13 g of 4,5-dichloro-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone, 6.70 g of 3,4-dimethoxybenzylamine, 130 ml of 1,4-dioxane and 130 ml of water, was refluxed with stirring overnight. The solvent was evaporated under reduced pressure, and water was poured to the residue, whereupon the product was extracted with chloroform. The extract was washed with dilute hydrochloric acid, water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-n-hexane-diethyl ether to obtain 5.28 g of the above identified compound as colorless crystals having a melting point of from 111° C. to 112° C.

NMR δ: 11.71(1H,broad s), 6.71(3H,s), 5.02(1H,collapsed t), 4.76(2H,d), 4.11(2H,t), 3.80(6H,s), 3.57(3H,s), 2.26(2H,t), 2.1-1.2(6H,m).

MS(m/e):439(M+), 404, 151(100%).

PREPARATION EXAMPLE 2 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-carboxypentyloxy)-3(2H)-pyridazinone (Compound No. 2) ##STR41##

A mixture comprising 240 mg of 4-chloro-5-(3,4-dimethoxybenzylamino) -6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) prepared in Preparation Example 1, 65 mg of sodium hydroxide, 10 ml of methanol and 1 ml of water, was stirred at 60°-70° C. for 1 hour. After the reaction liquor was evaporated under reduced pressure, water was poured to the residue, and the resultant solution was adjusted to pH 1-2 with dilute hydrochloric acid, whereupon the product was extracted with chloroform. The extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 192 mg of the above identified compound as colorless crystals having a melting point of from 150.5° C. to 151.5° C.

NMR

δ: 6.70(3H,s), 5.14(1H,collapsed t), 4.75(2H,d), 4.10(2H,t), 3.79(6H,s), 2.29(2H,t), 2.0-1.2(6H,m).

IR: (ν_(max) ^(KBr) cm⁻¹): 3100, 2910, 1720, 1610.

MS(m/e): 425(M⁺), 390, 151(100%).

PREPARATION EXAMPLE 3 4-Bromo-5-(3-pyridylmethylamino)-6-(3-phenylpropoxy)-3(2H)-pyridazinone hydrochloride (Compound No. 85) ##STR42##

2.50 g of 4-bromo-5-(3-pyridylmethylamino)-6-(3-phenylpropoxy) -3(2H)-pyridazinone (Compound No. 101) was dissolved in 150 ml of a 10% hydrogen chloride methanol solution, and the resultant solution was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-diethyl ether to obtain 2.68 g of the above identified compound as colorless crystals having a melting point of from 203° C. to 205° C.

MS(m/e): 414(M⁺ -HCl), 335, 322, 296, 217, 118(100%).

PREPARATION EXAMPLE 4 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-N,N-diethylaminocarbonylpentyloxy) -3(2H)-pyridazinone (Compound No. 12) ##STR43##

60 mg of ethyl chlorocarbonate was added to a mixture comprising 200 mg of 4-chloro-5-(3,4-dimethoxybenzylamino) -6-(5-carboxypentyloxy)-3(2H)-pyridazinone (Compound No. 2) prepared in Preparation Example 2, 60 mg of triethylamine and 10 ml of tetrahydrofuran under cooling with ice, and the resultant mixture was stirred at the same temperature for 1.5 hours. 100 mg of diethylamine was further added thereto, and the resultant mixture was further stirred for 2.5 hours after removing the ice bath, and the solvent was evaporated under reduced pressure. Water was poured to the residue, and the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 209 mg of the above identified-compound as colorless crystals having a melting point of from 148° C. to 149.5° C.

NMR

δ: 6.75(3H,s), 5.15(1H,collapsed t), 4.79(2H,d), 4.15(2H,t), 3.83(6H,s), 3.81, 3.76(each 2H,q), 2.27(2H,t), 2.1-1.9(6H,m), 1.15, 1.10(each 3H,t).

MS(m/e): 480(M+), 445, 310, 275, 170(100%), 151.

PREPARATION EXAMPLE 5 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-N-methylaminocarbonylpentyloxy) -3(2H)-pyridazinone (Compound No. 8) ##STR44##

A mixture comprising 200 mg of 4-chloro-5-(3,4-dimethoxybenzylamino) -6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) prepared in Preparation Example 1, 2 ml of 40% methylamine aqueous solution and 6 ml of methanol was refluxed for 8 hours. The reaction mixture was evaporated under reduced pressure, and the product was extracted with chloroform. The extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 146 mg of the above identified compound as colorless crystals having a melting point of from 103° C. to 104° C.

NMR δ: 11.65(1H,broad s), 6.73(3H,s), 6.0-5.5(1H,broad m), 5.02(1H,collapsed t), 4.76(2H,d), 4.10(2H,t), 3.81(6H,s), 2.74(3H,d), 2.12(2H, collapsed t), 1.9-1.3(6H,m).

MS(m/e): 438(M⁺), 403, 310, 274, 151(100%), 128.

PREPARATION EXAMPLE 6 4-Chloro-5-(3-pyridylmethylamino)-6-[5-(1-piperidinocarbonylpentyloxy)]-3(2H)-pyridazinone fumarate (Compound No. 73) ##STR45##

A mixture comprising 1.0 g of 4-chloro-5-(3-pyridylmethylamino) -6-[5-(1-piperidinocarbonylpentyloxy)]-3(2H)-pyridazinone (Compound No. 33), 268 mg of fumaric acid and 20 ml of methanol was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the solid residue was crystallized from chloroformethylacetate to obtain 1.06 g of the above identified compound as colorless crystals having a melting point of from 156° C. to 158° C.

MS(m/e): 433[M⁺ -(CH--CO₂ H)₂ ], 398, 287, 251, 216, 182(100%).

PREPARATION EXAMPLE 7 4-Cyano-5-(3-pyridiylmethylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 107) ##STR46##

A mixture comprising 1.0 g of 4 bromo-5-(3-pyridylmethylamino) -6-[3-(4-chlorophenylpropoxy)]-3-(2H)-pyridazinone (Compound No. 106), 587 mg of copper cyanide and 20 ml of N-methylpyrrolidone was stirred at 120°-130° C. for 6 hours. After cooling the resultant mixture to room temperature, a saturated ammonium chloride aqueous solution was added thereto, whereupon the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from acetonitrile to obtain 313 mg of the above identified compound as slightly yellow crystals having a melting point of from 188° C. to 190° C.

MS(m/e) 395(M⁺), 350, 243, 152(100%), 124.

IR: (ν_(max) ^(KBr) cm⁻¹): 3100, 2850, 2200, 1620.

PREPARATION EXAMPLE 8 2-Ethoxycarbonylmethyl-4-bromo-5-(3,4-dimethoxybenzylamino) -6-[3-(4-chlorophenylpropoxy)]3(2H)-pyridazinone (Compound No. 238) ##STR47##

A mixture comprising 100 mg of 4-bromo-5-(3,4-dimethoxybenzylamino) -6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 239), 33 mg of potassium carbonate, 49 mg of ethyl bromoacetate, 316 mg of sodium iodine and 5 ml of methyl ethyl ketone, was stirred under reflux for 5 hours. After removing the undissolved material by filtration, the solvent was evaporated under reduced pressure, and water was poured to the residue, whereupon the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elute: n-hexane/ethyl acetate=1/l) to obtain 82 mg of the above identified compound as colorless oil.

MS(m/e): 593(M⁺), 514, 288, 259, 151(100%).

PREPARATION EXAMPLE 9 2-(Carboxymethyl)-4-bromo-5-(3,4-dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 227) ##STR48##

A mixture comprising 80 mg of 2-ethoxycarbonylmethyl-4-bromo-5-(3,4-dimethoxybenzylamino) -6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 238) prepared in Preparation Example 8, 16 mg of sodium hydroxide, 2 ml of methanol and 0.2 ml of water, was stirred at room temperature for 2 hours After the reaction liquor was evaporated under reduced pressure, water was poured to the residue, and the resultant solution was adjusted to pH 1-2 with dilute hydrochloric acid, whereupon the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 49 mg of the above identified compound as colorless crystals having a melting point of from 140° C. to 141° C.

MS(m/e): 486(M⁺ -Br), 427, 371, 151(100%).

PREPARATION EXAMPLE 10 4-Bromo-5-[3-(N-oxypyridylmethylamino)]-6-(3-phenylpropoxy) -3(2H)-pyridazinone (Compound No. 230) ##STR49##

A mixture comprising 250 mg of 4-bromo-5-(3-pyridylmethylamino) -6-(3-phenylpropoxy)-3(2H)-pyridazinone, 167 mg of meta-chloroperbenzoic acid, and 10 ml of dichloromethane, was stirred at room temperature for 6 hours. To the resultant mixture, were added a saturated sodium hydrogencarbonate aqueous solution and chloroform, and the organic layer was separated. The remaining aqueous layer was reextracted with chloroform, and this extract was combined with the former organic layer. The combined extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting solid residue was crystallized from chloroformdiethyl ether to obtain the above identified compound as colorless crystals having a melting point of from 191° C. to 192° C.

MS(m/e): 414(M⁺ -O), 335, 323, 295, 217, 91(100%).

Compounds described in the following Table II were prepared in accordance with the above Preparation Examples. The structures of the compounds should be referred to Compound Numbers as shown in Table I. The most right column of Table II indicates Preparation Example Numbers applied.

                                      TABLE II                                     __________________________________________________________________________     Compound                                                                             Melting                      Example                                     No.   point (°C.)                                                                      MS (m/e)            No.                                         __________________________________________________________________________     1     111˜112                                                                           see Example 1       1                                           2     150.5˜151.5                                                                       see Example 2       1                                           3     111.5˜112.5                                                                       380(M.sup.+), 345(100%)                                                                            1                                           4     195˜195.5                                                                         366(M.sup.+), 92(100%)                                                                             2                                           5     171˜172                                                                           338(M.sup.+), 92(100%)                                                                             1                                           6     240˜240.5                                                                         292(M.sup.+ -H.sub.2 O), 92(100%)                                                                  2                                           7     194˜198                                                                           324(M.sup.+ -HCl), 92(100%)                                                                        3                                           8     103˜104                                                                           see Example 5       5                                           9     179˜180                                                                           452(M.sup.+), 151(100%)                                                                            4                                           10    167˜167.5                                                                         424(M.sup.+), 151(100%)                                                                            4                                           11    164˜165                                                                           494(M.sup.+), 184(100%)                                                                            4                                           12    148˜149.5                                                                         see Example 4       4                                           13    155˜156                                                                           520(M.sup.+), 210(100%)                                                                            4                                           14    135.5˜136.5                                                                       425(M.sup.+), 151(100%)                                                                            1                                           15    167˜168.5                                                                         397(M.sup.+), 151(100%)                                                                            2                                           16    163˜164                                                                           424(M.sup.+), 151(100%)                                                                            4                                           17    136˜138                                                                           452(M.sup.+), 151(100%)                                                                            4                                           18    181˜181.5                                                                         466(M.sup.+), 155(100%)                                                                            4                                           19    167˜168                                                                           397(M.sup.+), 151(100%)                                                                            1                                           20    192˜194                                                                           369(M.sup.+), 151(100%)                                                                            2                                           21    182˜185                                                                           542(M.sup.+), 151(100%)                                                                            1                                           22    163˜165                                                                           483(M.sup.+), 92(100%)                                                                             1                                           23    200˜201                                                                           494(M.sup.+), 151(100%)                                                                            1                                           24    Solid    435(M.sup.+), 217(100%)                                                                            1                                           25    108˜108.5                                                                         508(M.sup.+), 198(100%)                                                                            4                                           26    189˜190                                                                           492(M.sup.+), 182(100%)                                                                            4                                           27    201˜201.5                                                                         478(M.sup.+), 168(100%)                                                                            4                                           28    163˜164                                                                           421(M.sup.+), 170(100%)                                                                            4                                           29    173˜175                                                                           393(M.sup.+), 142(100%)                                                                            4                                           30    108.5˜109                                                                         467(M.sup.+), 151(100%)                                                                            1                                           31    132.5˜133                                                                         418(M.sup.+ -Cl), 151(100%)                                                                        1                                           32    165˜166                                                                           419(M.sup.+), 168(100%)                                                                            4                                           33    173.5˜176                                                                         433(M.sup.+), 182(100%)                                                                            4                                           34    169.5˜170                                                                         480(M.sup.+), 170(100%)                                                                            4                                           35    145˜146.5                                                                         508(M.sup.+), 198(100%)                                                                            4                                           36    127˜128                                                                           536(M.sup.+), 226(100%)                                                                            4                                           37    162˜163                                                                           506(M.sup.+), 151(100%)                                                                            4                                           38    163.5˜164                                                                         520(M.sup.+), 151(100%)                                                                            4                                           39    157.5˜158                                                                         522(M.sup.+), 151(100%)                                                                            4                                           40    145˜145.5                                                                         423(M.sup.+), 135(100%)                                                                            1                                           41    125˜126                                                                           483(M.sup.+), 151(100%)                                                                            1                                           42    166˜167                                                                           469(M.sup.+), 151(100%)                                                                            2                                           43    144˜144.5                                                                         496(M.sup.+), 151(100%)                                                                            4                                           44    180˜180.5                                                                         522(M.sup.+), 151(100%)                                                                            4                                           45    161˜161.5                                                                         536(M.sup.+), 151(100%)                                                                            4                                           46    114˜116                                                                           524(M.sup.+), 170(100%)                                                                            4                                           47    136-137  552(M.sup.+), 198(100%)                                                                            4                                           48    135˜136                                                                           538(M.sup.+), 151(100%)                                                                            4                                           49    157˜158                                                                           409(M.sup.+), 135(100%)                                                                            2                                           50    153˜155                                                                           464(M.sup.+), 151(100%)                                                                            4                                           51    114˜116                                                                           461(M.sup.+), 217(100%)                                                                            4                                           52    Hygroscopic solid                                                                       461(M.sup.+ -HCl), 217(100%)                                                                       3                                           53    103˜104                                                                           436(M.sup.+), 135(100%)                                                                            4                                           54    123˜124                                                                           464(M.sup.+), 170(100%)                                                                            4                                           55    124˜125                                                                           492(M.sup.+), 198(100%)                                                                            4                                           56    148˜149                                                                           462(M.sup.+), 168(100%)                                                                            4                                           57    144˜145                                                                           476(M.sup.+), 182(100%)                                                                            4                                           58    121˜122                                                                           478(M.sup.+), 135(100%)                                                                            4                                           59    121˜122                                                                           432(M.sup.+ -Br), 151(100%)                                                                        1                                           60    118˜119                                                                           478(M.sup.+), 151(100%)                                                                            4                                           61    187-187.5                                                                               506(M.sup.+), 196(100%)                                                                            4                                           62    165.5˜166                                                                         534(M.sup.+), 98(100%)                                                                             4                                           63    156.5˜157                                                                         524(M.sup.+), 170(100%)                                                                            4                                           64    133˜133.5                                                                         552(M.sup.+), 198(100%)                                                                            4                                           65    116˜116.5                                                                         580(M.sup.+), 226(100%)                                                                            4                                           66    148.5˜150                                                                         550(M.sup.+), 196(100%)                                                                            4                                           67    150˜151                                                                           564(M.sup.+), 210(100%)                                                                            4                                           68    141˜142                                                                           566(M.sup.+), 487(100%)                                                                            4                                           69     87˜89                                                                            419(M.sup.+), 84(100%)                                                                             4                                           70    Solid    463(M.sup.+), 84(100%)                                                                             4                                           71    112˜114                                                                           478(M.sup.+), 168(100%)                                                                            4                                           72    170˜173                                                                           433(M.sup.+ -HCl), 182(100%)                                                                       3                                           73    156˜158                                                                           see Example 6       6                                           74    160˜162                                                                           461(M.sup.+), 210(100%)                                                                            4                                           75    Hygroscopic solid                                                                       461(M.sup.+ -HCl), 210(100%)                                                                       3                                           76    135˜137                                                                           461[M.sup.+ -(CH--CO.sub.2 H).sub.2 ], 210(100%)                                                   6                                           77    142˜144                                                                           433(M.sup.+), 182(100%)                                                                            4                                           78    Hygroscopic solid                                                                       405(M.sup.+ -HCl), 153(100%)                                                                       3                                           79    Hygroscopic solid                                                                       433(M.sup.+ -HCl), 182(100%)                                                                       3                                           80    178˜181                                                                           400(M.sup.+ -HCl), 105(100%)                                                                       3                                           81    Hygroscopic solid                                                                       419(M.sup.+ -HCl), 168(100%)                                                                       3                                           82    Hygroscopic solid                                                                       463(M.sup.+ -HCl), 168(100%)                                                                       3                                           83    121˜123                                                                           459(M.sup.+), 380(100%)                                                                            1                                           84    154˜156                                                                           473(M.sup.+), 394(100%)                                                                            1                                           85    203˜205                                                                           see Example 3       3                                           86    133˜134                                                                           588(M.sup.+), 278(100%)                                                                            4                                           87     95˜96                                                                            616(M.sup.+), 180(100%)                                                                            4                                           88    106˜107                                                                           528(M.sup.+), 154(100%)                                                                            1                                           89    211˜212                                                                           410(M.sup.+), 92(100%)                                                                             2                                           90    152˜154                                                                           429(M.sup.+), 151(100%)                                                                            1                                           91    134˜135                                                                           370(M.sup.+), 91(100%)                                                                             1                                           92    190˜202                                                                           370(M.sup.+ -HCl), 91(100%)                                                                        3                                           93    166˜172                                                                           370[M.sup.+ -(CH--CO.sub.2 H).sub.2 ], 91(100%)                                                    6                                           94    105˜106                                                                           380, 182(100%)      1                                           95    145.5˜146                                                                         211(100%), 141      1                                           96    155˜156                                                                           276, 211(100%)      1                                           97    169˜170                                                                           296, 211(100%)      1                                           98    132˜132.5                                                                         515(M.sup.+ -Br), 170(100%)                                                                        1                                           99    149˜150                                                                           535(M.sup.+), 170(100%)                                                                            1                                           100   142˜143                                                                           211(100%), 141      1                                           101   130˜133                                                                           414(M.sup.+), 91(100%)                                                                             1                                           102   118˜119                                                                           428(M.sup.+), 91(100%)                                                                             1                                           103   146˜147                                                                           408(M.sup.+ -Br), 151(100%)                                                                        1                                           104   203˜205                                                                           471(M.sup.+), 106(100%)                                                                            1                                           105   153.5˜154                                                                         404(M.sup.+), 125(100%)                                                                            1                                           106   148˜150                                                                           448(M.sup.+), 151(100%)                                                                            1                                           107   188˜190                                                                           see Example 7       7                                           108   156.5˜157                                                                         480(M.sup.+), 126(100%)                                                                            1                                           109   142˜143                                                                           522(M.sup.+), 126(100%)                                                                            1                                           110   139.5˜140                                                                         421(M.sup.+), 126(100%)                                                                            1                                           111   173˜174                                                                           435(M.sup.+), 140(100%)                                                                            1                                           112   142.5˜144                                                                         494(M.sup.+), 140(100%)                                                                            1                                           113   209˜214                                                                           485(M.sup.+ -HCl), 190(100%)                                                                       3                                           114   173˜175                                                                           296[M.sup.+ -(CH.sub.2).sub.3 CONHPh], 161(100%)                                                   4                                           115   218.5˜219                                                                         205[M.sup.+ -((CH.sub.2).sub.3 CON-Q96, CH.sub.2 -Q23)],                                           4                                                          151(100%)                                                       116   233˜234                                                                           205[M.sup.+ -(CH.sub.2).sub.3 CONH-Q97],                                                           4                                                          151(100%)                                                       117   216˜216.5                                                                         551(M.sup.+), 151(100%)                                                                            4                                           118   132˜134                                                                           437(M.sup.+), 142(100%)                                                                            4                                           119   131˜132                                                                           505(M.sup.+), 210(100%)                                                                            4                                           120   129˜130                                                                           354[M.sup.+ -(CH.sub.2).sub.3 CONMe-Q2],                                                           4                                                          151(100%)                                                       121    97˜104                                                                           499(M.sup.+ -HCl), 204(100%)                                                                       3                                           122   141˜144                                                                           392(M.sup.+ -Br), 76(100%)                                                                         4                                           123   105˜110                                                                           513(M.sup.+ -HCl), 218(100%)                                                                       3                                           124   153˜155                                                                           485(M.sup.+), 190(100%)                                                                            4                                           125   110˜111                                                                           572(M.sup.+), 218(100%)                                                                            4                                           126   186˜193                                                                           479(M.sup.+ -HCl), 184(100%)                                                                       3                                           127   199˜201                                                                           451(M.sup.+), 156(100%)                                                                            4                                           128   176˜176.5                                                                         568(M.sup.+), 258(100%)                                                                            4                                           129   145˜147                                                                           471(M.sup.+), 105(100%)                                                                            1                                           130   164˜165                                                                           530(M.sup.+ ), 151(100%)                                                                           4                                           131   101˜103                                                                           463(M.sup.+), 98(100%)                                                                             1                                           132   137˜140                                                                           449(M.sup.+), 98(100%)                                                                             1                                           133   152˜152.5                                                                         522(M.sup.+), 151(100%)                                                                            1                                           134   123˜123.5                                                                         477(M.sup.+), 398(100%)                                                                            1                                           135   Amorphous                                                                               463(M.sup.+ -HCl), 168(100%)                                                                       3                                           136   142˜143                                                                           459(M.sup.+), 45(100%)                                                                             1                                           137   129.5˜131                                                                         522(M.sup.+), 168(100%)                                                                            1                                           138   192˜193.5                                                                         431(M.sup.+), 136(100%)                                                                            1                                           139   119˜119.5                                                                         439(M.sup.+ -Br), 151(100%)                                                                        1                                           140   168˜170                                                                           490(M.sup.+), 151(100%)                                                                            1                                           141   192.5˜194                                                                         493(M.sup.+), 198(100%)                                                                            1                                           142   103˜109                                                                           521(M.sup.+), 184(100%)                                                                            1                                           143   164˜165                                                                           473(M.sup.+ -Br), 151(100%)                                                                        1                                           144   142˜143                                                                           501(M.sup.+ -Br), 151(100%)                                                                        1                                           145   168˜169                                                                           445(M.sup.+), 122(100%)                                                                            1                                           146   107˜108                                                                           473(M.sup.+), 98(100%)                                                                             1                                           147   179˜180                                                                           504(M.sup.+), 151(100%)                                                                            1                                           148   138.5˜139                                                                         453(M.sup.+ -Br), 151(100%)                                                                        1                                           149   139˜139.5                                                                         393(M.sup.+ -OMe), 98(100%)                                                                        1                                           150   134˜136                                                                           439(M.sup.+), 92(100%)                                                                             1                                           151   190˜191                                                                           411(M.sup.+), 116(100%)                                                                            1                                           152   153˜154                                                                           484(M.sup.+), 151(100%)                                                                            1                                           153    97˜99                                                                            498(M.sup.+), 151(100%)                                                                            1                                           154   107˜108                                                                           439(M.sup.+), 144(100%)                                                                            1                                           155   102.5˜104                                                                         453(M.sup.+), 102(100%)                                                                            1                                           156   122˜123                                                                           425(M.sup.+), 130(100%)                                                                            1                                           157   106.5˜107                                                                         498(M.sup.+), 151(100%)                                                                            1                                           158   134.5˜136                                                                         512(M.sup.+), 151(100%)                                                                            1                                           159   123˜124.5                                                                         451(M.sup.+), 100(100%)                                                                            1                                           160   129˜130                                                                           465(M.sup.+), 386(100%)                                                                            1                                           161   Oily substance                                                                          437(M.sup.+), 142(100%)                                                                            1                                           162   139˜140                                                                           524(M.sup.+), 151(100%)                                                                            1                                           163   133˜134.5                                                                         496(M.sup.+), 151(100%)                                                                            1                                           164   135˜142                                                                           395[M.sup.+ -(NHPh, HCl)], 119(100%)                                                               3                                           165   170˜177                                                                           398[M.sup.+ -(CONHPh, HCl)], 119(100%)                                                             3                                           166   188˜205                                                                           448(M.sup.+ -HCl), 151(100%)                                                                       3                                           167   184˜190                                                                           404(M.sup.+ -HCl), 125(100%)                                                                       3                                           168   153˜156                                                                           418(M.sup.+), 125(100%)                                                                            1                                           169   160˜161                                                                           448[M.sup.+ -(CH--CO.sub.2 H).sub.2 ], 151(100%)                                                   6                                           170   155˜156                                                                           448[M.sup.+ 1/2(HC(OH)CO.sub.2 H).sub.2 ],                                                         651(100%)                                   171   163˜165                                                                           448[M.sup.+ -1/2(CH--CO.sub.2 H).sub.2 ],                                                          651(100%)                                   172   178.5˜179.5                                                                       448[M.sup.+ -1/2(CO.sub.2 H).sub.2 ], 151(100%)                                                    6                                           173   112˜114                                                                           444(M.sup.+), 148(100%)                                                                            1                                           174   130˜131                                                                           458(M.sup.+), 121(100%)                                                                            1                                           175   103˜105                                                                           472(M.sup.+), 121(100%)                                                                            1                                           176   124˜126                                                                           428(M.sup.+), 121(100%)                                                                            1                                           177   150˜152                                                                           424(M.sup.+ -Br), 151(100%)                                                                        1                                           178   152˜154                                                                           487(M.sup.+ -Br), 184(100%)                                                                        1                                           179   103˜105                                                                           539(M.sup.+), 132(100%)                                                                            1                                           180   147˜151                                                                           460(M.sup.+), 164(100%)                                                                            1                                           181   205˜215                                                                           476(M.sup.+ -HCl), 217(100%)                                                                       1                                           182   129˜131                                                                           474(M.sup.+), 178(100%)                                                                            1                                           183   169˜170                                                                           533(M.sup.+), 151(100%)                                                                            1                                           184   126˜127                                                                           502(M.sup.+), 164(100%)                                                                            1                                           185   109˜111                                                                           561(M.sup.+), 151(100%)                                                                            1                                           186   131˜132                                                                           502(M.sup.+), 164(100%)                                                                            1                                           187   103˜105                                                                           561(M.sup.+), 151(100%)                                                                            1                                           188   188˜190                                                                           460(M.sup.+), 164(100%)                                                                            1                                           189   163.5˜164                                                                         519(M.sup.+), 151(100%)                                                                            1                                           190    85.5˜86                                                                          444(M.sup.+), 148(100%)                                                                            1                                           191   187˜188                                                                           472(M.sup.+), 147(100%)                                                                            1                                           192   149˜150.5                                                                         561(M.sup.+), 151(100%)                                                                            1                                           193   206˜210                                                                           420(M.sup. + -HCl), 97(100%)                                                                       3                                           194   209˜210                                                                           420(M.sup.+), 97(100%)                                                                             1                                           195   138˜142                                                                           479(M.sup.+), 151(100%)                                                                            1                                           196   143˜145                                                                           415(M.sup.+), 336(100%)                                                                            1                                           197   152.5˜153                                                                         474(M.sup.+), 151(100%)                                                                            1                                           198    91˜96                                                                            416(M.sup.+), 337(100%)                                                                            1                                           199   168˜168.5                                                                         475(M.sup.+), 151(100%)                                                                            1                                           200   134˜134.5                                                                         405(M.sup.+), 92(100%)                                                                             1                                           201   130.5˜131                                                                         464(M.sup.+), 151(100%)                                                                            1                                           202   116˜126                                                                           452(M.sup.+), 151(100%)                                                                            3                                           203   110˜120                                                                           442(M.sup.+), 58(100%)                                                                             3                                           204   179˜184                                                                           454(M.sup.+ -HCl), 86(100%)                                                                        3                                           205   115˜120                                                                           571(M.sup.+), 151(100%)                                                                            3                                           206   127˜132                                                                           605(M.sup.+), 151(100%)                                                                            3                                           207   160˜168                                                                           567(M.sup.+ -Br), 151(100%)                                                                        3                                           208   150˜151                                                                           413(M.sup.+), 135(100%)                                                                            1                                           209   144˜146                                                                           464(M.sup.+), 135(100%)                                                                            1                                           210   162˜163                                                                           428(M.sup.+), 91(100%)                                                                             1                                           211   181˜182                                                                           427(M.sup.+), 135(100%)                                                                            1                                           212   145˜146                                                                           519(M.sup.+), 135(100%)                                                                            1                                           213   156˜165                                                                           589(M.sup.+), 135(100%)                                                                            3                                           214   176˜179                                                                           252[M.sup.+ -CH.sub.2 C(Me.sub.2)CH.sub.2 -Q2],                                                    325(100%)                                   215   167˜168                                                                           392(M.sup.+ -Br), 135(100%)                                                                        1                                           216   190˜192                                                                           447(M.sup.+), 135(100%)                                                                            1                                           217   Oily substance                                                                          441(M.sup.+), 135(100%)                                                                            8                                           218    97˜98                                                                            455(M.sup.+), 135(100%)                                                                            8                                           219   147˜148                                                                           481(M.sup.+), 135(100%)                                                                            1                                           220   174˜177                                                                           462(M.sup.+), 125(100%)                                                                            1                                           221   131˜132                                                                           482(M.sup.+), 125(100%)                                                                            1                                           222   151˜153                                                                           432(M.sup.+), 155(100%)                                                                            1                                           223   141˜144                                                                           438(M.sup.+), 81(100%)                                                                             1                                           224   168˜169                                                                           418(M.sup.+ -Br) (100%)                                                                            1                                           225   149˜152                                                                           461(M.sup.+), 382(100%)                                                                            1                                           226   Oily substance                                                                          521(M.sup.+), 151(100%)                                                                            8                                           227   140˜141                                                                           see Example 9       9                                           228   108˜108.5                                                                         515(M.sup.+), 193(100%)                                                                            1                                           229   203˜205                                                                           471(M.sup.+), 106(100%)                                                                            1                                           230   191˜192                                                                           see Example 10      10                                          231   123˜125                                                                           521(M.sup.+), 105(100%)                                                                            1                                           232   112˜113                                                                           549(M.sup.+), 471(100%)                                                                            1                                           233   113˜115                                                                           549(M.sup.+), 471(100%)                                                                            1                                           234   146˜147                                                                           408(M.sup.+), 151(100%)                                                                            1                                           235   178˜181                                                                           492(M.sup.+), 121(100%)                                                                            1                                           236   178˜181                                                                           527(M.sup.+), 171(100%)                                                                            1                                           237   185˜189                                                                           399(M.sup. + -Br), 122(100%)                                                                       1                                           238   Oily substance                                                                          see Example 8       8                                           239   153˜154                                                                           428(M.sup.+ -Br), 151(100%)                                                                        1                                           240   Oily substance                                                                          518(M.sup.+ -Br), 105(100%)                                                                        1                                           __________________________________________________________________________

    ______________________________________                                         FORMULATION EXAMPLE 1 (Tablets)                                                ______________________________________                                         Compound No. 85          10     g                                              Lactose                  20     g                                              Starch                   4      g                                              Starch for paste         1      g                                              Magnesium stearate       0.1    g                                              Carboxymethyl cellulose calcium                                                                         7      g                                              Total                    42.1   g                                              ______________________________________                                    

The above components were mixed in a usual manner, and formulated into sugar-coated tablets each containing 50 mg of an active ingredient.

    ______________________________________                                         FORMULATION EXAMPLE 2 (Capsules)                                               ______________________________________                                         Compound No. 88         10    g                                                Lactose                 20    g                                                Microcrystal cellulose  10    g                                                Magnesium stearate      1     g                                                Total                   41    g                                                ______________________________________                                    

The above components were mixed in a usual manner, and filled into gelatin capsules to obtain capsules each containing 50 mg of an active ingredient.

    ______________________________________                                         FORMULATION EXAMPLE 3 (Soft capsules)                                          ______________________________________                                         Compound No. 94        10    g                                                 Corn oil               35    g                                                 Total                  45    g                                                 ______________________________________                                    

The above components were mixed and formulated in a usual manner to obtain soft capsules.

    ______________________________________                                         FORMULATION EXAMPLE 4 (Ointment)                                               ______________________________________                                         Compound No. 55     1.0    g                                                   Olive oil           20     g                                                   White vasoline      79     g                                                   Total               100    g                                                   ______________________________________                                    

The above components were mixed in a usual manner to obtain 1% ointment.

    ______________________________________                                         FORMULATION EXAMPLE 5 (Aerosol suspension)                                     ______________________________________                                         (A)     Compound No. 11       0.25%                                                    Isopropyl myristate   0.10%                                                    Ethanol               26.40%                                           (B)     A 60-40% mixture of 1,2-                                                                             73.25%                                                   dichlorotetrafluoroethane and                                                  1-chloropentafluoroethane                                              ______________________________________                                    

The above composition (A) was mixed. The solution mixture thereby obtained was charged in a container equipped with a valve, and the propellant (B) was injected from the valve nozzle to a gauge pressure of from about 2.46 to 2.81 mg/cm² to obtain an aerosol suspension.

Test Method

I. Anti-platelet aggregation effect

1. In vitro test

(A) Anti-platelet aggregation effect in rabbits

Blood was collected from the central artery of Japanese white male rabbits (weight: 1.8 to 2.5 kg) into a syringe containing 1/10 volume 3.8% sodium citrate. The blood thus obtained was subjected to a centrifuge at 200×g for 7 minutes at room temperature to obtain platelet rich plasma (PRP). furthermore, the residue was subjected to a centrifuge at 2000×g for 10 minutes to obtain platelet poor plasma (PPP). The measurement was effected by diluting PRP and PPP to 300,000/mm³. PRP and PPP were placed in a cuvette, and the measurement range of transmittance was adjusted to 0% in the case of PRP and to 100% in the case of PPP. Thereafter, a test sample drug dissolved in 100% dimethylsulfoxide (DMSO) was added to PRP (the final concentration of DMSO: 0.25%). After incubation was effected at 37° C., 900 rpm for 2 minutes, an aggregating agent was added to measure an aggregation curve. The anti-platelet aggregation effect of the test sample drug was expressed by a concentration (IC₅₀ : μM) at which the aggregation of control sample was 50% inhibited. The aggregating agents ADP and arachidonic acid (A.A.) were used at minimum concentrations (ADP: 5 to 10 μM: A.A.: 0.2 to 0.3 mM) which causes maximum aggregation. The measurement of platelet aggregation was carried out by using NBS HEMA TRACER 601.

(B) Anti-platelet aggregation effect in guinea-pigs

Blood was collected from the central artery of a Hartley type male guinea-pig (weight: about 300 g) in the same manner as above, and was subjected to a centrifuge at 160×g for 10 minutes at room temperature to obtain PRP. Furthermore, the residue was subjected to a centrifuge at 3000×g for 15 minutes. PRP for measurement was prepared in the same manner as in the above rabbit text example, and a test sample drug dissolved in 100% DMSO was added (DMSO final concentration: 0.5%) to calculate 50% aggregation-inhibiting concentration IC₅₀ value to a control sample. As the aggregating agent, A.A. having the final concentration of 0.2 mM was used.

2. In vivo test

(A) Anti-platelet aggregation effect in rabbits

After a Japanese white male rabbit (weight: 1.8 to 2.5 kg) was fasted for 18 hours, a test sample drug suspended in 0.5% methyl cellulose was orally administered thereto. After administration, blood was periodically collected from ear artery, and PRP was prepared in the same manner as in the above in vitro test to measure platelet aggregation caused by each aggregating agent. The effect of the test sample drug was evaluated by inhibited aggregation ratio calculated on the assumption that the aggregation before administration was 100%.

(B) Anti-platelet aggregation effect on guinea-pigs

(1) After a Hartley type male guinea-pig (weigh: around 350 g) was fasted for 18 hours, a test sample drug suspended in a 5% gum arabic solution was orally administered thereto. After administration, blood was collected periodically from central artery, and PRP was prepared in the same manner as in the above in vitro test to measure platelet aggregation caused by each aggregating agent. The effect of the test sample drug was evaluated by inhibited aggregation ratio calculated on the assumption that the aggregation before administration was 100%.

(2) After a Hartley type male guinea-pig (weight: around 350 g) was fasted for 18 hours, a test sample drug suspended in a 5% gum arabic solution was orally administered thereto. One hour after the administration, blood was collected from central artery, and PRP was prepared in the same manner as in the above in vitro test to measure platelet aggregation caused by each aggregating agent. The effect of the test sample drug was evaluated by inhibited aggregation ratio calculated on the assumption that the aggregation before administration was 100%.

(C) Thrombocytopenia model of mouse

Collagen (Hormon-Chemie Co., Ltd.) diluted in an isotonic sodium chloride solution was administered to an ICR male mouse (weight: 24-30 g) through the tail vein in an amount of 1 mg/5 ml/kg. Five minutes later, under pentobarbital anesthesia, 9 volume amounts of blood was collected from inferior vena cava into a plastic syringe containing one volume amount of 3.8% sodium citrate. A test sample drug was orally administered one hour before the administration of collagen. The blood thus collected was diluted 20 times with Isotone II, and was subjected to a centrifuge at 60×g for 5 minutes. Thereafter the upper layer was further diluted with Isotone II to measure the number of platelets by a coulter counter (model ZM).

In the above tests I-1 and I-2, ticlopidine hydrochloride (Daiichi Seiyaku Co., Ltd.) and Cilostazol (Otsuka Pharmaceutical Co., Ltd.) were used as control drugs.

II. Cardiotonic effect

After exsanguinating a male guinea-pig (Hartley type, 250-400 g), the heart was taken out and was immediately dipped in a nutrition solution (Kreb's-Henseleit solution : NaCl 118.4 mM, KCl 4.7 mM, MgSO₄.7H₂ O 1.18 mM, CaCl₂.2H₂ O 2.5 mM, KH₂ PO₄ 1.2 mM, NaHCO₃ 24.9 mM, Glucose 11.1 mM) aerated with oxygen (containing 5% of carbon dioxide). Thereafter, the oxygen-aerated nutrition solution was placed in a laboratory dish for preparing a sample, and oxygen was continuously aerated. After rapidly separating the atrium and the ventricle, a papillary muscle sample was prepared from the right ventricle, and was suspended in an organ bath filled with the oxygen-aerated nutrition solution maintained at 31° C., then 500 mg of tension being loaded thereto.

After suspending the papillary muscle sample, the nutrition solution was replaced 20 minutes later and 40 minutes later, and after observing for further 20 minutes, isoproterenol was accumulatively administered (the final concentration: 3×10⁻⁷ M) to observe the effect on the contractile force. After repeating the procedure after suspending once more in the same manner as above, the nutrition solution was replaced 20 minutes later and 40 minutes later, and after observing for further 20 minutes, a test sample drug was accumulatively administered. The effect of each test sample drug on contractile force was evaluated by change ratio (%) caused by the test sample drug on the assumption that the difference in contractile force at the second isoproterenol administration was 100%, and a concentration EC₃₀ (μM) necessary for making 30% increase was calculated.

The measurement of contractile force was conducted by applying rectangular pulses [voltage: threshold value×2 (V), duration: 3 (msec), frequency: 1 (Hz)] onto the papillary muscle through bipolar platinum electrodes by an electronic stimulator (Nihon Kohden SEN-3201) to record the generated tension on a recorder by a F-D pickup and strain gage.

As a control cardiotonics, a Milrinone (Winthrop Co.) was used.

III. Vasodilatory effect

A male rabbit (Japanese white type, 2-2.5 kg) was subjected to anesthesia by intravenous injection of nembutal [weight (kg)×0.5+0.5 ml]. After exsanguination, the thoracic aorta was taken out and was immediately dipped in a nutrition solution (Kreb's-Henseleit solution: NaCl 118.4 mM, KCl 4.7 mM, MgSO₄.7H₂ O 1.188 mM, CaCl₂.2H₂ O 2.5 mM, KH₂ PO₄ 1.2 mM, NaHCO₃ 24.9 mM, Glucose 11.1 mM) aerated with oxygen (containing 5% of carbon dioxide). Thereafter, it was placed in a laboratory dish for preparing a sample, which was filled with the oxygen-aerated nutrition solution, and both ends of the blood vessel were fixed by pins to remove fat and connective tissue. A spiral sample (width: 3 mm, length: about 1 cm) was prepared by cutting with scissors. The both sides of the sample was fixed by a clip, and was suspended in an organ bath filled with the oxygen-aerated nutrition solution and maintained at 37° C., then a tension of 2 g being loaded thereon.

The tension of the blood vessel was recorded on a recorder (Nihon Kohden) by means of an F-D pickup (Nihon Kohden 611-T) and strain gage (Nihon Kohden AP-600G).

After suspending, the nutrition solution was replaced 20 minutes later and 40 minutes later, and each sample was observed for further 20 minutes (during which the tension was maintained 2 g). Thereafter, norepinephrine was administered (final concentration: 10⁻⁶ M) and the blood vessel influenced by tension was observed. After the contraction became stable, the nutrition solution was replaced, and the nutrition solution was further replaced 20 minutes later and 40 minutes later. After observing for further 20 minutes, the blood vessel was contracted by a contractile agent. After the contraction became stable, a test sample drug was accumulatively administered. After finishing the test, papaverine was administered (final concentration: 10⁻⁴ M) to achieve complete relaxation.

The effect of the test sample drug on contraction by the contractile agent was evaluated by a change ratio (%) caused by the test sample drug on the assumption that the difference in tension between at the time of administration of the contractile agent and after the administration of papaverine was 100%.

IV. Anti-SRS-A effect (bronchodilating effect) Drug:

A test sample drug was used by dissolving and diluting in 100% dimethylsulfoxide (DMSO, Wako Junyaku). Leukotriene D₄ (LTD₄, Ultrafine) was diluted with distilled water.

Indomethacin (Indo, Sigma) was dissolved in 100% ethanol (EtOH, Komune Kagaku). Aminophylline (AP, Sigma), histamine dihydrochloride (His, Wako Junyaku) was dissolved in distilled water. The final concentrations of DMSO and EtOH in a bath were made respectively not higher than 0.25% v/v and not higher than 0.1% v/v.

Method

A guinea-pig of 300-450 g was exsanguinated, and the trachea was taken out. After removing fat and connective tissue, it was cut into spiral strips having a width of about 2 mm and was divided into 2 to 3 pieces, each containing 4 smooth muscle tissues. The sample thus prepared was suspended in an organ bath of 8 ml containing a modified Tyrode solution aerated with 95% O₂ +5% CO₂ at 37° C., and 1 g of load was applied thereon. The relaxation of the muscle was recorded by a pen recorder (Yokogawa Hokushin Electric, type 3066) by means of an isotonic transducer (Nihon Kohden, TD-112S).

The composition of the modified Tyrode solution was as follows (mM):

NaCl 137, KCl 2.7, CaCl₂ 1.8, MgCl₂ 1.0, NaHCO₃ 20, NaH₂ PO₄ 0.32, Glucose 11.

The sample was allowed to stand for 50-60 minutes, and was contracted with histamine dihydrochloride (10 μM). After the reaction became constant, it was washed and allowed to stand for 20-30 minutes. Indomethacin (5 μM) was added to the sample, and after incubation for 30 minutes, the sample was contracted by adding LTD₄ (30 nM). After the reaction became stable, a test drug was accumulatively administered. Finally AP (1 mM) was added to achieve maximum relaxtant reaction. The result was expressed by relaxation percent on the assumption that the relaxation by AP was 100%, and a concentration to achieve 50% relaxation (EC₅₀, μM) was measured.

As a control drug, FPL-55712 recognized as a selective SRS-A antagonistic agent was used [(Fisons Ltd.); Journal of Medicinal chemistry, Vol 20, pp. 371-379, 1977].

TEST RESULTS

I Anti-platelet aggregation effect

1. In vitro test: (A), (B)

Tables III-1 to III-3 show anti-platelet aggregation effects of test compounds evaluated as IC₅₀ values (μM).

                  TABLE III-1                                                      ______________________________________                                         Test Compound    Rabbit PRP; IC.sub.50                                         No.              ADP     A.A.                                                  ______________________________________                                         1                0.22    0.5                                                   Cilostazol       28.0    8.8                                                   ______________________________________                                    

                  TABLE III-2                                                      ______________________________________                                         Test                  Test                                                     Compound                                                                               Rabbit PRP    Compound  Rabbit PRP                                     No.     ADP; IC.sub.50                                                                               No.       ADP; IC.sub.50                                 ______________________________________                                         9       0.32          143       0.25                                           11      0.85          153       0.61                                           12      0.93          158       0.22                                           13      0.52          162       0.053                                          21      6.0           166       0.14                                           26      0.16          167       0.14                                           27      0.24          169       0.064                                          29      0.58          173       0.15                                           30      0.29          177       0.042                                          36      0.45          178       0.1                                            38      0.52          180       0.12                                           42      18.0          183       0.03                                           47      0.05          181       0.024                                          48      0.15          188       0.24                                           54      2.7           190       0.29                                           61      0.19          192       0.081                                          70      0.43          195       0.48                                           76      1.2           199       0.72                                           85      0.10          206       0.64                                           86      0.33          210       0.14                                           120     0.6           230       0.18                                           133     0.18          239       0.16                                           137     0.13          Cilostazol                                                                               28.0                                           ______________________________________                                    

                  TABLE III-3                                                      ______________________________________                                         Test                                                                           Compound     Guinea-pig PRP                                                    No.          A.A.; IC.sub.50                                                   ______________________________________                                         85           0.026                                                             88           0.018                                                             94           0.018                                                             99           0.18                                                              Cilostazol   1.4                                                               ______________________________________                                    

2. in vivo test

(A) Anti-platelet aggregation effect in rabbits

                                      TABLE III-4                                  __________________________________________________________________________     Test   Administration                                                                              Aggregation-                                                                          Average ratio of                                    Compound                                                                              amount  Example                                                                             causing                                                                               anti-platelet aggregation (%)                       No.    (mg/kg) number                                                                              agent  1 hr.  3 hrs.                                       __________________________________________________________________________     72     50      2    ADP    57     59                                           72     50      2    A.A.   98     86                                           75     50      2    ADP    65     31                                           75     50      2    A.A.   76     21                                           Ticlopidine                                                                           300     3    ADP    24     37                                           hydrochloride                                                                  Tichlopidine                                                                          300     3    A.A.   13     2                                            hydrochloride                                                                  __________________________________________________________________________

(B) Anti-platelet aggregation effect in guinea-pigs (1)

                                      TABLE III-5                                  __________________________________________________________________________     Test   Administration                                                                              Aggregation-                                                                          Average ratio of                                    Compound                                                                              amount  Example                                                                             causing                                                                               anti-platelet aggregation (%)                       No.    (mg/kg) Number                                                                              agent  1 hr.  3 hrs.                                       __________________________________________________________________________     166    10      3    A.A.   85     58                                           181    30      1    A.A.   69     71                                           158    30      1    A.A.   68     35                                           __________________________________________________________________________

Anti-platelet aggregation effect in guinea pigs (2)

                  TABLE III-6                                                      ______________________________________                                         Test    Administration                                                                             Aggregation-                                                                              Ratio of anti-                                  Compound                                                                               amount      causing    platelet aggregation                            No.     (mg/kg)     agent      (%)                                             ______________________________________                                         85      3           A.A.       57.8                                            92      10          A.A.       92.5                                            152     10          A.A.       93.1                                            166     3           A.A.       93.1                                            181     10          A.A.       88.6                                            169     10          A.A.       92.7                                            ______________________________________                                    

(C) Effect of inhibiting reduction in platelets of mice

                  TABLE III-7                                                      ______________________________________                                         Test     Administration        Average inhibiting                              Compound amount      Example   ratio                                           No.      (mg/kg)     number    (%)                                             ______________________________________                                         38       30         5          31.4*                                           52       30         5          51.1*                                           84       10         5          55.0**                                          85       30         5          36.6*                                           Ticlopidine                                                                             300        6          30.1*                                           hydrochloride                                                                  Ticlopidine                                                                             100        6          13.7                                            hydrochloride                                                                  Cilostazol                                                                              100        5          39.4*                                           Cilostazol                                                                              30         6          18.3                                            ______________________________________                                          *.sup.1 Significant difference from control value was statistically            recognized at the ratio of risk of 5% (* mark) and at the ratio of risk o      1% (** mark).                                                            

II. Cardiotonic effect

                  TABLE IV                                                         ______________________________________                                         Test       Contractile  Maximum reaction                                       Compound   force of     ratio                                                  No.        heart EC.sub.30 (μM)                                                                     (μM)                                                ______________________________________                                         11         11.2         57.7 (300)                                             44         20.6         51.0 (300)                                             Milrinone  33.9         59.1 (300)                                             ______________________________________                                          *.sup.2 Maximum contractile force is expressed by reaction rate to             contractile force of isoproterenol, and numerical value in parenthesis         indicates minimum concentration (measured at 300 μM) at that time.    

III. Vasodilatory effect

                  TABLE V                                                          ______________________________________                                                   Vasodilatory                                                         Test      effect         EC.sub.30 (μM)                                     Compound  NE*.sup.3      U-46619  PGF.sub.2 α                            No.       10.sup.-6 M    10.sup.-7 M                                                                             10.sup.-6 M                                  ______________________________________                                         11        0.363          2.19     0.447                                        Papaverine                                                                               4.37           10.5     8.71                                         ______________________________________                                          *.sup.3 NE = norepinephrine                                              

IV. Anti-SRS-A effect

                  TABLE VI                                                         ______________________________________                                         Test                  Test                                                     Compound              Compound                                                 No.       EC.sub.50   No.        EC.sub.50                                     ______________________________________                                         12        0.023       55         0.068                                         13        0.40        75         0.21                                          16        0.28        84         0.025                                         21        0.26        94         0.059                                         23        0.23        96         0.56                                          28        0.42        FPL-55712  0.10                                          ______________________________________                                    

INDUSTRIAL APPLICABILITY

As evident from the above results, it is clear that the compound of the present invention has excellent anti-platelet aggregation effect, cardiotonic effect, vasodilatory effect and anti-SRS-A effect. Thus, the compound of the present invention can be useful prophylactic and therapeutic drugs for various thrombotic diseases, congestive heart failure, hypertension, angina pectoris, and immediate type allergy diseases including asthma. 

We claim:
 1. A 3(2H)-pyridazinone of the formula: ##STR50## wherein R¹ is a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₃ -C₄ alkenyl group or (CH₂)_(n) CO₂ R⁵ where n is an integer from 1 to 4, R⁵ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group;R¹ is A¹ -Y¹ where A¹ is a straight chain or branched C₁ -C₁₂ alkylene group, Y¹ is CO₂ R⁵, a cyano group, OR⁶ where R⁶ is a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group or a phenyl group, a thienyl or pyridyl group, ##STR51## where R⁷ and R⁸ are independently a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group, a phenyl group, a thiazolyl or thiadiazolyl group, or R⁷ and R⁸ together form a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain or branched C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom, ##STR52## where R⁵ is as defined above and R⁹ is a straight chain or branched C₁ -C₄ alkyl group or a phenyl group which is unsubstituted or substituted with a straight chain or branched C₁ -C₄ alkyl group or a halogen atom, ##STR53## where R¹⁰ and R¹¹ are independently a hydrogen atom, a halogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₁ -C₄ acylamino group, OR⁵, NHSO₂ R⁹ or S(O)_(m) --R¹² where m is an integer from 0 to 2 and R¹² is a straight chain or branched C₁ -C₄ alkyl group, provided that R¹⁰ and R¹¹ are not hydrogen atoms at the same time, ##STR54## where R¹³ is a hydrogen atom and R¹⁴ is a phenyl group, or R¹³ and R¹⁴ together form a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group, ##STR55## where R¹⁵ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group, R¹⁶ is a straight chain or branched C₁ -C₄ alkyl group, or R¹⁵ and R¹⁶ together form a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group, ##STR56## where R¹⁷ and R¹⁸ are independently a straight chain or branched C₁ -C₄ alkyl group, or R¹⁷ and R¹⁸ together form a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group, ##STR57## where l is 1 or 2, k is an integer from 0 to 3, and R¹⁹ is a hydrogen atom or a halogen atom, or ##STR58## or R² is A² -Y² where A² is a C₂ -C₁₀ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group, except where a carbon chain connecting an oxygen atom with Y² has one carbon, and Y² is a phenyl group; R³ and R⁴ are independently a hydrogen atom or a straight chain or branched C₁ -C₃ alkyl group; X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; and Ar is ##STR59## where j is 0 or 1 and R²⁰ is a hydrogen atom, a halogen atom or OR¹² where R¹² is as defined above, ##STR60## where Z¹ is an oxygen atom or sulfur atom; and a pharmaceutically acceptable salt thereof.
 2. A 3(2H)-pyridazinone compound according to claim 1, wherein R⁴ is a hydrogen atom and X is a chlorine atom, a bromine atom or a cyano group; and a pharmaceutically acceptable salt thereof.
 3. A 3(2H)-pyridazinone compound according to claim 2 of the formula: ##STR61## wherein R¹ is a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, or (CH₂)_(n) CO₂ R⁴ where n is an integer from 1 to 4, R⁴ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group;R² is A¹ -Y¹ where A¹ is a straight chain or branched C₁ -C₁₂ alkylene group, Y¹ is CO₂ R⁴, a cyano group, a phenoxy group, a thienyl or pyridyl group, ##STR62## where R⁵ and R⁶ are independently a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group, a phenyl group, a thiazolyl or thiadiazolyl group, or R⁵ and R⁶ together form a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain or branched C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom, ##STR63## where R⁴ is as defined above, R⁷ is a straight chain or branched C₁ -C₄ alkyl group or a phenyl group which is unsubstituted or substituted with a halogen atom, ##STR64## where R⁸ and R⁹ are independently a hydrogen atom, a halogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₁ -C₄ acylamino group, OR⁴, NHSO₂ R¹⁰ where R¹⁰ is a straight chain or branched C₁ -C₄ alkyl group or S(O)_(m) --R¹⁰ where m is an integer from 0 to 2 and R¹⁰ is as defined above, provided that R⁸ and R⁹ are not hydrogen atoms at the same time, ##STR65## where R¹¹ is a hydrogen atom and R¹² is a phenyl group, or R¹¹ and R¹² together form a C₂ -C₅ alkylene group, ##STR66## where R¹³ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group, R¹⁴ is a straight chain or branched C₁ -C₄ alkyl group, or R¹³ and R¹⁴ together form a C₁ -C₄ alkylene group, ##STR67## where R¹⁵ and R¹⁶ are independently a straight chain or branched C₁ -C₄ alkyl group, or R¹⁵ and R¹⁶ together form a C₂ -C₆ alkylene group, ##STR68## where 1 is 1 or 2, R¹⁷ is a hydrogen atom or a halogen atom, or ##STR69## or R² is A² -Y² where A² is a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group, except where a carbon chain connecting an oxygen atom with Y² has one carbon, and Y² is a phenyl group; R³ is a hydrogen atom, or a straight chain or branched C₁ -C₃ alkyl group; X is a chlorine atom, a bromine atom, or a cyano group; and Ar is ##STR70## where k is 0 or 1 and R¹⁸ is a hydrogen atom, a halogen atom or OR¹⁰ where R¹⁰ is a straight chain or branched C₁ -C₄ alkyl group, ##STR71## where Z¹ is an oxygen atom or sulfur atom; and a pharmaceutically acceptable salt thereof.
 4. A 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 3, wherein R¹ and R³ are hydrogen atoms.
 5. An anti-thrombotic, ionotropic, vasodilatory or anti-SRS-A agent comprising a pharmaceutically effective amount of a the 3(2H)-pyridazinone compound or its pharmaceutically acceptable salt as defined in claim 1 in combination with a pharmaceutically acceptable carrier.
 6. The 3(2H)-pyridazinone compound according to claim 1 of the formula: ##STR72## wherein R² is A¹ -Y¹ where A¹ is a straight chain or branched C₁ -C₇ alkylene group, and Y¹ is CO₂ R⁴ where R⁴ is selected from the group consisting of a hydrogen atom and a straight chain or branched C₁ -C₄ alkyl group; ##STR73## where R⁵ and R⁶ are the same or different and are selected from the group consisting of a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, and a C₃ -C₈ cycloalkyl group, or R⁵ and R⁶ together form a C₄ -C₆ alkylene group which is unsubstituted or substituted with methyl group or from a morpholine ring with a nitrogen atom; ##STR74## where R⁸ and R⁹ are the same or different and are selected from the group consisting of a hydrogen atom, a halogen atom, and OR⁴, provided that R⁸ and R⁹ are not hydrogen atoms at the same time; ##STR75## where R¹³ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group, R¹⁴ is a straight chain or branched C₁ -C₄ alkyl group, or R¹³ and R¹⁴ together form a C₂ -C₄ alkylene group; or R² is A² -Y² where A² is a C₂ -C₇ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group, except where a carbon chain connecting an oxygen atom with Y² has one carbon; and Y² is a phenyl group;X is a chlorine atom or a bromine atom; and Ar is pyridyl; and a pharmaceutically acceptable thereof.
 7. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Chloro-6-(5-N,N-diethylaminocarbonylpentyloxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 8. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Chloro-6-(5-methoxycarbonylpentyloxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 9. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Bromo-6-(5-(1-morpholinocarbonyl)pentyloxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 10. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Bromo-6-(5-N-methoxycarbonyl-N-methylaminopentyloxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 11. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 12. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Bromo-6-(3-(4-methoxyphenyl)propoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 13. The 3(2H-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Chloro-6-(3-(4-chlorophenyl)propoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 14. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.
 15. The 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 1, which is 4-Bromo-6-(3-(4-chlorophenyl)methylbutoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone. 